半胱氨酰白三烯CysLT_2受体通过激活小胶质细胞介导神经元缺血性损伤
|
摘要
研究背景：
半胱氨酰白三烯(cysteinyl leukotrienes, CysLTs)是一类重要的炎症介质,包括白三烯C4(leukotrienes C4, LTC4)、LTD4和LTE4。CysLTs通过半胱氨酰白三烯受体(cysteinyl leukotriene receptor, CysLT受体)起作用,包括CysLT1和CysLT2受体两种亚型。在外周,CysLT1受体参与多种炎症性疾病,如支气管哮喘、过敏性鼻炎等；CysLT2受体增加血管通透性,增强心肌缺血再灌注损伤。在中枢,大鼠局灶性脑缺血损伤后的脑组织,以及原代培养神经元和星形胶质细胞在缺氧缺糖(oxygen-glucose deprivation, OGD)后,CysLTs释放增加。局灶性脑缺血后,CysLT1和CysLT2受体表达显著上调,急性期(24h)主要分布在损伤的神经元,慢性期(3-28d)主要分布在激活的小胶质细胞及增生的星形胶质细胞,提示CysLT1和CysLT2受体介导急性期神经元损伤和慢性期小胶质细胞和星形胶质细胞增生。
在细胞水平,CysLT1和CysLT2受体转染对大鼠肾上腺嗜铬细胞瘤细胞株PC12细胞缺血性损伤有不同调节作用,即转染CysLT1受体后对OGD敏感性降低,转染CysLT2受体后对OGD敏感性增加。然而,CysLT,和CysLT2受体是否介导缺血性神经损伤,尚待研究。在原代培养的大鼠皮层神经元,OGD能诱导神经元损伤,但CysLT受体激动剂LTD4并不诱导神经元损伤,不能证明整体实验的结果。因此,CysLTs很可能通过作用于神经元周围的细胞间接调节神经元损伤,例如,星形胶质细胞和小胶质细胞。我们已发现CysLT1和CysLT2受体在星形胶质细胞的不同调节作用,但对于它们如何调节小胶质细胞还有待研究。
药理学研究表明,CysLT1受体选择性拮抗剂pranlukast和montelukast对大鼠、小鼠的局灶性和全脑缺血等损伤均有保护作用,可减轻神经元损伤、血脑屏障破坏、炎症反应、慢性脑损伤和胶质疤痕形成等。但是,montelukast不能减轻OGD诱导的神经元活性下降,仅能改善OGD后神经元形态变化。另一方面,长期缺乏CysLT2受体选择性拮抗剂,使得该受体在神经元缺血性损伤中的作用未得到充分研究。目前,已有CysLT2受体选择性激动剂N-methyl leukotriene C4(NMLTC4),以及CysLT2受体选择性拮抗剂Bay CysLT2和HAMI3379,为研究CysLT2受体提供了有用的工具。我们新近报道,HAMI3379对大鼠局灶性脑缺血有明显的保护作用,但其在细胞水平对脑缺血损伤的作用还需进一步研究。
研究目的：
本文拟较系统地研究CysLT,和CysLT2受体对OGD诱导的神经元缺血性损伤的调节作用,一是观察其直接作用,二是观察其通过胶质细胞激活的间接作用。具体解决以下四方面问题：(1)在大鼠原代神经元,两种受体是否直接调节缺血性损伤?(2)大鼠皮层混合细胞中,两种受体对缺血性损伤有何作用?(3)大鼠原代神经元-胶质细胞共培养中,两种受体对神经元缺血性损伤有何作用?(4)在大鼠原代小胶质细胞,两种受体对其吞噬功能、细胞因子释放有何作用?包括阐明其条件培养液对神经元损伤的影响。
研究方法：
在大鼠原代皮层神经元、皮层细胞混合培养、神经元-胶质细胞Transwell培养或小胶质细胞培养中,以缺氧缺糖(OGD)诱导缺血性损伤,以不同浓度非选择性激动剂LTD4或CysLT2受体选择性激动剂NMLTC4诱导损伤性变化；观察CysLT1受体选择性拮抗剂孟鲁斯特(montelukast)、CysLT2受体选择性拮抗剂HAMI3379的药理学效应。并以siRNA靶向沉默CysLT1受体表达,以慢病毒shRNA靶向沉默CysLT2受体表达。观察激动剂、拮抗剂及RNA干扰对OGD诱导的原代皮层神经元、皮层混合细胞、神经元-胶质细胞共培养的神经元损伤,或小胶质细胞激活及吞噬的影响。
研究结果：
第一部分CysLT1和CysLT2受体对皮层神经元OGD/R诱导损伤的影响
首先,确定CysLTs是否通过其受体直接参与神经元缺血性损伤的调节。OGD时间依赖性诱导大鼠皮层神经元损伤,而非选择性激动剂LTD4、CysLT2受体激动剂NMLTC4不诱导神经元损伤。Montelukast可以减轻OGD/R (OGD1h,恢复24h)诱导的神经元损伤,表现为减轻神经元存活率下降、LDH释放以及坏死等；而HAMI3379则无这些作用。此外,经RT-PCR及WB证实,本研究采用的siRNA能成功抑制神经元CysLT1受体表达,慢病毒shRNA成功抑制CysLT2受体表达；但是,CysLT1受体siRNA和CysLT2受体shRNA均不能抑制神经元OGD/R损伤。
这些结果提示,CysLTs及其受体并不直接参与调节神经元缺血性损伤,montelukast的抗脑缺血作用可能是一种非CysLT1受体依赖的作用。
第二部分CysLT1和CysLT2受体对皮层细胞混合细胞OGD/R诱导损伤的影响
为阐明在相对完整的细胞环境中CysLT受体的调节作用,我们观察了皮层细胞混合培养中的变化。OGD/R (OGD1h,恢复24h),LTD4, NMLTC4诱导细胞活性下降,LDH释放,细胞凋亡和坏死增加,小胶质细胞激活。CysLT2受体shRNA及CysLT2受体选择性拮抗剂HAMI3379可抑制细胞活性下降及LDH释放,减少坏死细胞数目,对凋亡没有明显影响。免疫荧光染色结果显示,细胞死亡以神经元死亡为主,星形胶质细胞和小胶质细胞死亡较少,CysLT2受体shRNA及HAMI3379可减少神经元死亡,抑制小胶质细胞激活。Montelukast可以减轻OGD/R或LTD4诱导的上述变化,但CysLT,受体siRNA却无此作用。
上述结果提示,CysLT2受体介导皮层细胞混合培养中OGD诱导的神经元损伤和小胶质细胞激活,表明小胶质细胞激活与神经元损伤密切相关；但CysLT1受体不介导这些反应,montelukast可能通过非CysLT1受体依赖途径抑制神经元损伤和小胶质细胞激活。
第三部分CysLT1和CysLT2受体对神经元-胶质共培养中OGD/R诱导神经元损伤的影响
为进一步阐明小胶质细胞激活与神经元损伤的关系,我们观察了神经元-胶质细胞在Transwell共培养中的变化。在神经元-星形胶质细胞共培养中,OGD,LTD4, NMLTC4诱导神经元损伤,神经元数量减少,坏死细胞增多。而CysLT1受体siRNA、 montelukast、 CysLT2受体shRNA和HAMI3379对此均无明显作用。在神经元-小胶质细胞共培养中,OGD, LTD4, NMLTC4诱导神经元损伤,神经元数量减少,坏死细胞增多；这些变化可被CysLT2受体shRNA和HAMI3379减轻。Montelukast亦抑制OGD或LTD4诱导神经元-小胶质细胞共培养中神经元损伤,CysLT1受体siRNA对LTD4诱导的损伤也有部分抑制作用。
上述结果提示,CysLT2受体通过小胶质细胞介导神经元损伤,并且,是一种主要调节途径。CysLT1受体部分通过小胶质细胞参与神经元损伤的调节；montelukast可能通过CysLT1受体依赖和非依赖途径抑制神经元损伤。但是,CysLT受体通过星形胶质细胞的调节作用尚待进一步研究。
第四部分CysLT1和CysLT2受体对原代小胶质细胞OGD/R诱导的小胶质细胞激活,以及小胶质细胞条件培养液对神经元损伤的影响
为阐明CysLT受体对小胶质细胞的调节作用,我们观察了原代培养大鼠小胶质细胞的变化。免疫荧光染色显示,静息状态下CysLT,和CysLT2受体表达较少,OGD/R(OGD1h,恢复24h)诱导CysLT1和CysLT2表达上调。CysLT2受体shRNA和HAMI3379可抑制OGD/R, LTD4, NMLTC4诱导的小胶质细胞激活、吞噬以及细胞因子TNF-α、IL-1β的释放。Montelukast可抑制OGD/R或LTD4诱导的小胶质细胞激活、吞噬；而CysLT1受体siRNA仅部分抑制细胞因子的释放。另一方面,OGD/R, LTD4, NMLTC4预处理的小胶质细胞培养液,可诱导神经元坏死；该变化可被HAMI3379和CysLT2受体shRNA抑制。Montelukast有减轻OGD/R和LTD4诱导神经元坏死的趋向；而CysLT1受体siRNA无此作用。
这些结果提示,CysLT2受体作为主要因素通过调节小胶质细胞激活(增强吞噬以及细胞因子释放),进而介导神经元损伤。而CysLT1受体部分参与调节细胞因子释放；montelukast可能通过CysLT1受体依赖和非依赖途径介导神经元损伤。
结论：
1. CysLTs及其受体不直接参与OGD/R诱导的大鼠原代皮层神经元缺血性损伤。
2.在大鼠皮层细胞混合培养中,CysLT2受体介导OGD/R诱导的神经元损伤和小胶质细胞激活；而CysLT1受体作用不明显。在神经元-胶质细胞共培养中,CysLT2受体作为主要因素通过调节小胶质细胞激活,介导OGD/R诱导的神经元损伤；CysLT1受体部分参与调节；CysLT受体对的星形胶质细胞作用尚待阐明。
3. CysLT2受体可调节OGD/R诱导的小胶质细胞激活,通过增强吞噬及细胞因子释放,介导神经元损伤；CysLT1受体部分介导小胶质细胞细胞因子释放的效应。
4. HAMI3379可拮抗CysLT2受体的效应；montelukast既有CysLT1受体非依赖的作用,也有CysLT1受体依赖的作用。它们均具有抗脑缺血损伤炎症效应的潜在价值。
Backgrounds
Cysteinyl leukotrienes (CysLTs), namely leukotriene C4(LTC4), LTD4and LTE4, are arachidonic acid-derived lipid mediators. CysLTs act on least two G protein-coupled receptors, CysLT1R and CysLT2R, and play important regulatory roles. In the periphery, the CysLT1R is involved in various inflammatory diseases such as bronchial asthma and allergic rhinitis, and the CysLT2R mediates increase of vascular permeability and aggravates myocardial ischemia/reperfusion injury. In the central nervous system (CNS), the production of CysLTs increases after ischemic injury in rat brain, primary neurons and astrocytes. Increased CysLTs induce various CNS responses through activating their receptors. It has been reported that the expression of CysLT1R and CysLT2R was up-regulated in the brain after focal cerebral ischemia. These up-regulated receptors were distributed in injured neurons in the acute phase (-24h), and activated microglia and proliferating astrocytes in the late phases (3-28days). These findings suggest that CysLT1R and CysLT2R may mediate acute ischemic neuronal injury and the sequential microgliosis and astrocytosis in vivo.
In cellular level, neuron-like PC12cells transfected with CysLT1R and CysLT2R showed distinct sensitivities to ischemic injury, namely CysLT1R transfection lowered, but CysLT2R transfection increased, the sensitivity to ischemia-like injury induced by oxygen-glucose deprivation (OGD). However, whether and how these receptors regulate ischemic neuronal injury is necessary to be investigated. In primary neurons, OGD induced injury, but the agonist LTD4of CysLT receptors did not induce ischemia-like injury, which cannot explain the in vivo findings. Therefore, it is possible that CysLTs may regulate ischemic neuronal injury via interactions between neurons and surrounding cells, such as astrocyte and microglia. We have found that CysLT1R and CysLT2R play distinct roles in regulation of astrocytes; however, their roles in regulation of microglial activation need investigation.
Pharmacologically, the CysLT1R antagonists pranlukast and montelukast have protective effects on focal or global cerebral ischemia in rats and mice. They attenuated neuronal injury, blood-brain barrier disruption, inflammatory responses, chronic brain injury and the relevant glial scar formation. However, montelukast had no effect on OGD-induced reduction in neuron viability, or merely moderate effect on neuron morphological changes after OGD. On the other hand, because of lack of selective CysLT2R antagonists for a long time, their effects on ischemic neuronal injury are unknown. Recently, N-methyl leukotriene C4(NMLTC4) has been reported as a potent selective agonist for the CysLT2receptor, and Bay CysLT2and HAMI3379as selective CysLT2R antagonists, which provide useful tools for CysLT2R investigation. We have reported that intracerebroventricular injection of HAMI3379protects rats from acute brain injury after focal cerebral ischemia, but its effects on in vitro ischemic neuronal injury need investigation.
Aims
In the present study, we investigated the detailed regulatory roles of CysLTiR and CysLT2R in OGD-induced ischemic neuronal injury, including the direct action on neurons and the indirect action through activating microglia. We performed cellular experiments to answer the following questions:(1) In primary rat cortical neurons, whether CysLT receptor subtypes directly mediate OGD-induced injury?(2) In mixed cultures of rat cortical cells, whether CysLT receptor subtypes mediate OGD-induced cell injury?(3) In neuron-glial transwell co-cultures, whether CysLT receptor subtypes mediate OGD-induced neuronal injury through interactions with astrocyte or microglia?(4) In primary rat microglia, whether CysLT receptor subtypes mediate OGD-induced microglial activation (phagocytosis and cytokine release) and thereby induce neuronal injury? The effects of microglial conditioned medium on neuronal injury were also included.
Methods
In primary rat cortical neuron, the mixed cultures of rat cortical cells, neuron-glial transwell co-cultures and rat primary microglia, ischemic injury was induced by OGD. The agonist LTD4or NMLTC4at various concentrations was applied as stimuli to induce neuronal injury. The effects of the CysLT1R antagonist montelukast and the CysLT2R antagonist HAMI3379were observed as well. The gene expression of CysLTiR was silenced by a targeted siRNA and that of CysLT2R was silenced by a targeted lentivirus shRNA. Thus, OGD-induced neuronal injury and microglia activation were investigated by application of the agonists, antagonists and RNA interference of CysLT1R and CysLT2R.
Results
Part I Roles of CysLT1R and CysLT2R in OGD-induced injury in primary rat cortical neurons
At first, we determined whether CysLTs directly affect primary neurons via activating their receptors. The results showed that OGD time-dependently induced ischemic neuronal injury, while the non-selective agonist LTD4and the selective CysLT2R agonist NMLTC4did not induce neuronal injury. The CysLT1R antagonist montelukast attenuated OGD/R (OGD1h, recovery24h)-induced injury, including attenuation of neuronal viability reduction, LDH release and necrosis. However, the selective CysLT2R antagonist HAMI3379did not show these protective effects. In addition, inhibition of CysLT1R expression by CysLT1R siRNA and CysLT2R expression by CysLT2R shRNA had been confirmed in the neurons. Neither CysLT1R siRNA nor CysLT2R shRNA inhibited OGD/R-induced neuronal injury.
These findings indicated that CysLTs and their receptors might not directly mediate neuronal injury; the effects of montelukast might result from CysLT1R-independent mechanisms..
Part Ⅱ Roles of CysLT1R and CysLT2R in OGD-induced injury in the mixed cultures of cortical cells
Next, we determined whether CysLT receptor subtypes regulate OGD-induced injury in a relatively intact cellular environment, namely in the mixed cultures of cortical cells. We found that OGD/R (OGD1h, recovery24h), LTD4or NMLTC4induced cell viability reduction, LDH release increase, cell necrosis and apoptosis, and morphological changes of microglial activation. CysLT2shRNA and HAMI3379inhibited OGD/R-, LTD4-or NMLTC4-induced responses. Montelukast, not CysLT1R siRNA, attenuated the changes induced by OGD/R and LTD4.
Therefore, CysLT2R might mediate neuronal injury and microglial activation in the mixed cultures of cortical cells, suggesting a close relationship between microglial activation and neuronal injury. CysLT1R might not mediate these responses, while montelukast partially inhibited neuronal injury and microglial activation through CysLT1R-independent mechanisms.
Part Ⅲ Roles of CysLT1R and CysLT2R in OGD-induced neuronal injury in neuron-glial co-cultures
Then, to further confirm the relation between microglial activation and neuronal injury, we observed the changes in neuron-glial transwell co-cultures. In neuron-astrocyte co-cultures, OGD/R (OGD1h, recovery24h), LTD4and NMLTC4induced mild neuronal injury, i.e. reduction in neuron number and induction of necrosis. None of the CysLT receptor antagonists and RNA interference affected these changes in neuron-astrocyte co-cultures. However, in neuron-microglial co-cultures, OGD/R, LTD4or NMLTC4induced more profound neuronal injury. CysLT2R shRNA and HAMI3379significantly decreased neuronal injury in neuron-microglial co-cultures. In neuron-microglial co-cultures, montelukast attenuated neuronal injury induced by OGD/R or LTD4, and CysLT1R siRNA had mild inhibition on LTD4-induced injury as well.
These findings indicated that CysLT2R might mediate the neuronal injury mediated by microglial activation, which might be the primary way for regulating ischemic neuronal injury. CysLT1R might partially regulate microglial activation, and montelukast might inhibit microglia-mediated neuronal injury through both CysLT1R-dependent and independent mechanisms. However, whether and how CysLT receptors regulate neuronal injury mediated by astrocytes remains to be investigated.
Part Ⅳ Roles of CysLT1R and CysLT2R in OGD-induced microglial activation, and effects of microglial conditioned medium on neuronal injury
Finally, to reveal the regulatory roles of CysLT receptors in microglial action, we observed the changes in primary cultures of rat microglia. Immunofluoresence examination showed that CysLT1R and CysLT2R were weakly expressed in microglia under normal conditions; and their expression was significantly up-regulated after OGD/R (1-h OGD and24-h recovery). OGD/R, LTD4or NMLTC4induced microglial activation, i.e. enhancing phagocytosis and increasing cytokine (TNF-a and IL-1β) release. HAMI3379and CysLT2shRNA inhibited all the responses induced by the three stimuli. Montelukast decreased the responses induced by OGD/R and LTD4, while CysLT1R siRNA partially inhibited cytokine release. On the other hand, the conditioned medium from microglia pre-treated with OGD/R, LTD4or NMLTC4induced neuronal necrosis, and CysLT2shRNA and HAMI3379inhibited the induced necrosis. Montelukast showed an inhibitory trend but no significant effect on OGD/R-and LTD4-induced necrosis, while CysLT1R siRNA had no effect.
These findings demonstrated that the CysLT2R, as the primary regulatory factor, might mediate microglial activation (enhancing phagocytosis and cytokine release), and thereby induce neuronal injury. CysLT1R might partially regulate cytokine release from microglia, and montelukast might inhibit neuronal injury through CysLT1R-dependent and independent mechanisms.
Conclusions:
1. In primary rat cortical neurons, CysLTs and their receptors do not directly mediate OGD/R-induced ischemic injury.
2. In the mixed cultures of rat cortical cells, CysLT1R, but not CysLT1R, mediates OGD/R-induced neuronal injury and microglial activation. In neuron-glial co-cultures, CysLT2R as the primary factor mediates OGD/R-induced neuronal injury via activating microglia, while CysLT1R partially regulates cytokine release from microglia; but the roles of CysLT receptors in astrocyte-mediated neuronal injury need investigation.
3. CysLT2R mediates OGD/R-induced microglial activation, and thereby induces neuronal injury via enhancing microglial phagocytosis and cytokine release. CysLT1R partially mediates neuronal injury via regulating cytokine release from microglia.
4. HAMI3379blocks CysLT2R-mediated responses, but montelukast exerts both CysLT1R-independent and dependent effects. Both of them may be potentially valuable for inhibition of inflammation after ischemic stroke.
半胱氨酰白三烯(cysteinyl leukotrienes, CysLTs)是一类重要的炎症介质,包括白三烯C4(leukotrienes C4, LTC4)、LTD4和LTE4。CysLTs通过半胱氨酰白三烯受体(cysteinyl leukotriene receptor, CysLT受体)起作用,包括CysLT1和CysLT2受体两种亚型。在外周,CysLT1受体参与多种炎症性疾病,如支气管哮喘、过敏性鼻炎等；CysLT2受体增加血管通透性,增强心肌缺血再灌注损伤。在中枢,大鼠局灶性脑缺血损伤后的脑组织,以及原代培养神经元和星形胶质细胞在缺氧缺糖(oxygen-glucose deprivation, OGD)后,CysLTs释放增加。局灶性脑缺血后,CysLT1和CysLT2受体表达显著上调,急性期(24h)主要分布在损伤的神经元,慢性期(3-28d)主要分布在激活的小胶质细胞及增生的星形胶质细胞,提示CysLT1和CysLT2受体介导急性期神经元损伤和慢性期小胶质细胞和星形胶质细胞增生。
在细胞水平,CysLT1和CysLT2受体转染对大鼠肾上腺嗜铬细胞瘤细胞株PC12细胞缺血性损伤有不同调节作用,即转染CysLT1受体后对OGD敏感性降低,转染CysLT2受体后对OGD敏感性增加。然而,CysLT,和CysLT2受体是否介导缺血性神经损伤,尚待研究。在原代培养的大鼠皮层神经元,OGD能诱导神经元损伤,但CysLT受体激动剂LTD4并不诱导神经元损伤,不能证明整体实验的结果。因此,CysLTs很可能通过作用于神经元周围的细胞间接调节神经元损伤,例如,星形胶质细胞和小胶质细胞。我们已发现CysLT1和CysLT2受体在星形胶质细胞的不同调节作用,但对于它们如何调节小胶质细胞还有待研究。
药理学研究表明,CysLT1受体选择性拮抗剂pranlukast和montelukast对大鼠、小鼠的局灶性和全脑缺血等损伤均有保护作用,可减轻神经元损伤、血脑屏障破坏、炎症反应、慢性脑损伤和胶质疤痕形成等。但是,montelukast不能减轻OGD诱导的神经元活性下降,仅能改善OGD后神经元形态变化。另一方面,长期缺乏CysLT2受体选择性拮抗剂,使得该受体在神经元缺血性损伤中的作用未得到充分研究。目前,已有CysLT2受体选择性激动剂N-methyl leukotriene C4(NMLTC4),以及CysLT2受体选择性拮抗剂Bay CysLT2和HAMI3379,为研究CysLT2受体提供了有用的工具。我们新近报道,HAMI3379对大鼠局灶性脑缺血有明显的保护作用,但其在细胞水平对脑缺血损伤的作用还需进一步研究。
研究目的：
本文拟较系统地研究CysLT,和CysLT2受体对OGD诱导的神经元缺血性损伤的调节作用,一是观察其直接作用,二是观察其通过胶质细胞激活的间接作用。具体解决以下四方面问题：(1)在大鼠原代神经元,两种受体是否直接调节缺血性损伤?(2)大鼠皮层混合细胞中,两种受体对缺血性损伤有何作用?(3)大鼠原代神经元-胶质细胞共培养中,两种受体对神经元缺血性损伤有何作用?(4)在大鼠原代小胶质细胞,两种受体对其吞噬功能、细胞因子释放有何作用?包括阐明其条件培养液对神经元损伤的影响。
研究方法：
在大鼠原代皮层神经元、皮层细胞混合培养、神经元-胶质细胞Transwell培养或小胶质细胞培养中,以缺氧缺糖(OGD)诱导缺血性损伤,以不同浓度非选择性激动剂LTD4或CysLT2受体选择性激动剂NMLTC4诱导损伤性变化；观察CysLT1受体选择性拮抗剂孟鲁斯特(montelukast)、CysLT2受体选择性拮抗剂HAMI3379的药理学效应。并以siRNA靶向沉默CysLT1受体表达,以慢病毒shRNA靶向沉默CysLT2受体表达。观察激动剂、拮抗剂及RNA干扰对OGD诱导的原代皮层神经元、皮层混合细胞、神经元-胶质细胞共培养的神经元损伤,或小胶质细胞激活及吞噬的影响。
研究结果：
第一部分CysLT1和CysLT2受体对皮层神经元OGD/R诱导损伤的影响
首先,确定CysLTs是否通过其受体直接参与神经元缺血性损伤的调节。OGD时间依赖性诱导大鼠皮层神经元损伤,而非选择性激动剂LTD4、CysLT2受体激动剂NMLTC4不诱导神经元损伤。Montelukast可以减轻OGD/R (OGD1h,恢复24h)诱导的神经元损伤,表现为减轻神经元存活率下降、LDH释放以及坏死等；而HAMI3379则无这些作用。此外,经RT-PCR及WB证实,本研究采用的siRNA能成功抑制神经元CysLT1受体表达,慢病毒shRNA成功抑制CysLT2受体表达；但是,CysLT1受体siRNA和CysLT2受体shRNA均不能抑制神经元OGD/R损伤。
这些结果提示,CysLTs及其受体并不直接参与调节神经元缺血性损伤,montelukast的抗脑缺血作用可能是一种非CysLT1受体依赖的作用。
第二部分CysLT1和CysLT2受体对皮层细胞混合细胞OGD/R诱导损伤的影响
为阐明在相对完整的细胞环境中CysLT受体的调节作用,我们观察了皮层细胞混合培养中的变化。OGD/R (OGD1h,恢复24h),LTD4, NMLTC4诱导细胞活性下降,LDH释放,细胞凋亡和坏死增加,小胶质细胞激活。CysLT2受体shRNA及CysLT2受体选择性拮抗剂HAMI3379可抑制细胞活性下降及LDH释放,减少坏死细胞数目,对凋亡没有明显影响。免疫荧光染色结果显示,细胞死亡以神经元死亡为主,星形胶质细胞和小胶质细胞死亡较少,CysLT2受体shRNA及HAMI3379可减少神经元死亡,抑制小胶质细胞激活。Montelukast可以减轻OGD/R或LTD4诱导的上述变化,但CysLT,受体siRNA却无此作用。
上述结果提示,CysLT2受体介导皮层细胞混合培养中OGD诱导的神经元损伤和小胶质细胞激活,表明小胶质细胞激活与神经元损伤密切相关；但CysLT1受体不介导这些反应,montelukast可能通过非CysLT1受体依赖途径抑制神经元损伤和小胶质细胞激活。
第三部分CysLT1和CysLT2受体对神经元-胶质共培养中OGD/R诱导神经元损伤的影响
为进一步阐明小胶质细胞激活与神经元损伤的关系,我们观察了神经元-胶质细胞在Transwell共培养中的变化。在神经元-星形胶质细胞共培养中,OGD,LTD4, NMLTC4诱导神经元损伤,神经元数量减少,坏死细胞增多。而CysLT1受体siRNA、 montelukast、 CysLT2受体shRNA和HAMI3379对此均无明显作用。在神经元-小胶质细胞共培养中,OGD, LTD4, NMLTC4诱导神经元损伤,神经元数量减少,坏死细胞增多；这些变化可被CysLT2受体shRNA和HAMI3379减轻。Montelukast亦抑制OGD或LTD4诱导神经元-小胶质细胞共培养中神经元损伤,CysLT1受体siRNA对LTD4诱导的损伤也有部分抑制作用。
上述结果提示,CysLT2受体通过小胶质细胞介导神经元损伤,并且,是一种主要调节途径。CysLT1受体部分通过小胶质细胞参与神经元损伤的调节；montelukast可能通过CysLT1受体依赖和非依赖途径抑制神经元损伤。但是,CysLT受体通过星形胶质细胞的调节作用尚待进一步研究。
第四部分CysLT1和CysLT2受体对原代小胶质细胞OGD/R诱导的小胶质细胞激活,以及小胶质细胞条件培养液对神经元损伤的影响
为阐明CysLT受体对小胶质细胞的调节作用,我们观察了原代培养大鼠小胶质细胞的变化。免疫荧光染色显示,静息状态下CysLT,和CysLT2受体表达较少,OGD/R(OGD1h,恢复24h)诱导CysLT1和CysLT2表达上调。CysLT2受体shRNA和HAMI3379可抑制OGD/R, LTD4, NMLTC4诱导的小胶质细胞激活、吞噬以及细胞因子TNF-α、IL-1β的释放。Montelukast可抑制OGD/R或LTD4诱导的小胶质细胞激活、吞噬；而CysLT1受体siRNA仅部分抑制细胞因子的释放。另一方面,OGD/R, LTD4, NMLTC4预处理的小胶质细胞培养液,可诱导神经元坏死；该变化可被HAMI3379和CysLT2受体shRNA抑制。Montelukast有减轻OGD/R和LTD4诱导神经元坏死的趋向；而CysLT1受体siRNA无此作用。
这些结果提示,CysLT2受体作为主要因素通过调节小胶质细胞激活(增强吞噬以及细胞因子释放),进而介导神经元损伤。而CysLT1受体部分参与调节细胞因子释放；montelukast可能通过CysLT1受体依赖和非依赖途径介导神经元损伤。
结论：
1. CysLTs及其受体不直接参与OGD/R诱导的大鼠原代皮层神经元缺血性损伤。
2.在大鼠皮层细胞混合培养中,CysLT2受体介导OGD/R诱导的神经元损伤和小胶质细胞激活；而CysLT1受体作用不明显。在神经元-胶质细胞共培养中,CysLT2受体作为主要因素通过调节小胶质细胞激活,介导OGD/R诱导的神经元损伤；CysLT1受体部分参与调节；CysLT受体对的星形胶质细胞作用尚待阐明。
3. CysLT2受体可调节OGD/R诱导的小胶质细胞激活,通过增强吞噬及细胞因子释放,介导神经元损伤；CysLT1受体部分介导小胶质细胞细胞因子释放的效应。
4. HAMI3379可拮抗CysLT2受体的效应；montelukast既有CysLT1受体非依赖的作用,也有CysLT1受体依赖的作用。它们均具有抗脑缺血损伤炎症效应的潜在价值。
Backgrounds
Cysteinyl leukotrienes (CysLTs), namely leukotriene C4(LTC4), LTD4and LTE4, are arachidonic acid-derived lipid mediators. CysLTs act on least two G protein-coupled receptors, CysLT1R and CysLT2R, and play important regulatory roles. In the periphery, the CysLT1R is involved in various inflammatory diseases such as bronchial asthma and allergic rhinitis, and the CysLT2R mediates increase of vascular permeability and aggravates myocardial ischemia/reperfusion injury. In the central nervous system (CNS), the production of CysLTs increases after ischemic injury in rat brain, primary neurons and astrocytes. Increased CysLTs induce various CNS responses through activating their receptors. It has been reported that the expression of CysLT1R and CysLT2R was up-regulated in the brain after focal cerebral ischemia. These up-regulated receptors were distributed in injured neurons in the acute phase (-24h), and activated microglia and proliferating astrocytes in the late phases (3-28days). These findings suggest that CysLT1R and CysLT2R may mediate acute ischemic neuronal injury and the sequential microgliosis and astrocytosis in vivo.
In cellular level, neuron-like PC12cells transfected with CysLT1R and CysLT2R showed distinct sensitivities to ischemic injury, namely CysLT1R transfection lowered, but CysLT2R transfection increased, the sensitivity to ischemia-like injury induced by oxygen-glucose deprivation (OGD). However, whether and how these receptors regulate ischemic neuronal injury is necessary to be investigated. In primary neurons, OGD induced injury, but the agonist LTD4of CysLT receptors did not induce ischemia-like injury, which cannot explain the in vivo findings. Therefore, it is possible that CysLTs may regulate ischemic neuronal injury via interactions between neurons and surrounding cells, such as astrocyte and microglia. We have found that CysLT1R and CysLT2R play distinct roles in regulation of astrocytes; however, their roles in regulation of microglial activation need investigation.
Pharmacologically, the CysLT1R antagonists pranlukast and montelukast have protective effects on focal or global cerebral ischemia in rats and mice. They attenuated neuronal injury, blood-brain barrier disruption, inflammatory responses, chronic brain injury and the relevant glial scar formation. However, montelukast had no effect on OGD-induced reduction in neuron viability, or merely moderate effect on neuron morphological changes after OGD. On the other hand, because of lack of selective CysLT2R antagonists for a long time, their effects on ischemic neuronal injury are unknown. Recently, N-methyl leukotriene C4(NMLTC4) has been reported as a potent selective agonist for the CysLT2receptor, and Bay CysLT2and HAMI3379as selective CysLT2R antagonists, which provide useful tools for CysLT2R investigation. We have reported that intracerebroventricular injection of HAMI3379protects rats from acute brain injury after focal cerebral ischemia, but its effects on in vitro ischemic neuronal injury need investigation.
Aims
In the present study, we investigated the detailed regulatory roles of CysLTiR and CysLT2R in OGD-induced ischemic neuronal injury, including the direct action on neurons and the indirect action through activating microglia. We performed cellular experiments to answer the following questions:(1) In primary rat cortical neurons, whether CysLT receptor subtypes directly mediate OGD-induced injury?(2) In mixed cultures of rat cortical cells, whether CysLT receptor subtypes mediate OGD-induced cell injury?(3) In neuron-glial transwell co-cultures, whether CysLT receptor subtypes mediate OGD-induced neuronal injury through interactions with astrocyte or microglia?(4) In primary rat microglia, whether CysLT receptor subtypes mediate OGD-induced microglial activation (phagocytosis and cytokine release) and thereby induce neuronal injury? The effects of microglial conditioned medium on neuronal injury were also included.
Methods
In primary rat cortical neuron, the mixed cultures of rat cortical cells, neuron-glial transwell co-cultures and rat primary microglia, ischemic injury was induced by OGD. The agonist LTD4or NMLTC4at various concentrations was applied as stimuli to induce neuronal injury. The effects of the CysLT1R antagonist montelukast and the CysLT2R antagonist HAMI3379were observed as well. The gene expression of CysLTiR was silenced by a targeted siRNA and that of CysLT2R was silenced by a targeted lentivirus shRNA. Thus, OGD-induced neuronal injury and microglia activation were investigated by application of the agonists, antagonists and RNA interference of CysLT1R and CysLT2R.
Results
Part I Roles of CysLT1R and CysLT2R in OGD-induced injury in primary rat cortical neurons
At first, we determined whether CysLTs directly affect primary neurons via activating their receptors. The results showed that OGD time-dependently induced ischemic neuronal injury, while the non-selective agonist LTD4and the selective CysLT2R agonist NMLTC4did not induce neuronal injury. The CysLT1R antagonist montelukast attenuated OGD/R (OGD1h, recovery24h)-induced injury, including attenuation of neuronal viability reduction, LDH release and necrosis. However, the selective CysLT2R antagonist HAMI3379did not show these protective effects. In addition, inhibition of CysLT1R expression by CysLT1R siRNA and CysLT2R expression by CysLT2R shRNA had been confirmed in the neurons. Neither CysLT1R siRNA nor CysLT2R shRNA inhibited OGD/R-induced neuronal injury.
These findings indicated that CysLTs and their receptors might not directly mediate neuronal injury; the effects of montelukast might result from CysLT1R-independent mechanisms..
Part Ⅱ Roles of CysLT1R and CysLT2R in OGD-induced injury in the mixed cultures of cortical cells
Next, we determined whether CysLT receptor subtypes regulate OGD-induced injury in a relatively intact cellular environment, namely in the mixed cultures of cortical cells. We found that OGD/R (OGD1h, recovery24h), LTD4or NMLTC4induced cell viability reduction, LDH release increase, cell necrosis and apoptosis, and morphological changes of microglial activation. CysLT2shRNA and HAMI3379inhibited OGD/R-, LTD4-or NMLTC4-induced responses. Montelukast, not CysLT1R siRNA, attenuated the changes induced by OGD/R and LTD4.
Therefore, CysLT2R might mediate neuronal injury and microglial activation in the mixed cultures of cortical cells, suggesting a close relationship between microglial activation and neuronal injury. CysLT1R might not mediate these responses, while montelukast partially inhibited neuronal injury and microglial activation through CysLT1R-independent mechanisms.
Part Ⅲ Roles of CysLT1R and CysLT2R in OGD-induced neuronal injury in neuron-glial co-cultures
Then, to further confirm the relation between microglial activation and neuronal injury, we observed the changes in neuron-glial transwell co-cultures. In neuron-astrocyte co-cultures, OGD/R (OGD1h, recovery24h), LTD4and NMLTC4induced mild neuronal injury, i.e. reduction in neuron number and induction of necrosis. None of the CysLT receptor antagonists and RNA interference affected these changes in neuron-astrocyte co-cultures. However, in neuron-microglial co-cultures, OGD/R, LTD4or NMLTC4induced more profound neuronal injury. CysLT2R shRNA and HAMI3379significantly decreased neuronal injury in neuron-microglial co-cultures. In neuron-microglial co-cultures, montelukast attenuated neuronal injury induced by OGD/R or LTD4, and CysLT1R siRNA had mild inhibition on LTD4-induced injury as well.
These findings indicated that CysLT2R might mediate the neuronal injury mediated by microglial activation, which might be the primary way for regulating ischemic neuronal injury. CysLT1R might partially regulate microglial activation, and montelukast might inhibit microglia-mediated neuronal injury through both CysLT1R-dependent and independent mechanisms. However, whether and how CysLT receptors regulate neuronal injury mediated by astrocytes remains to be investigated.
Part Ⅳ Roles of CysLT1R and CysLT2R in OGD-induced microglial activation, and effects of microglial conditioned medium on neuronal injury
Finally, to reveal the regulatory roles of CysLT receptors in microglial action, we observed the changes in primary cultures of rat microglia. Immunofluoresence examination showed that CysLT1R and CysLT2R were weakly expressed in microglia under normal conditions; and their expression was significantly up-regulated after OGD/R (1-h OGD and24-h recovery). OGD/R, LTD4or NMLTC4induced microglial activation, i.e. enhancing phagocytosis and increasing cytokine (TNF-a and IL-1β) release. HAMI3379and CysLT2shRNA inhibited all the responses induced by the three stimuli. Montelukast decreased the responses induced by OGD/R and LTD4, while CysLT1R siRNA partially inhibited cytokine release. On the other hand, the conditioned medium from microglia pre-treated with OGD/R, LTD4or NMLTC4induced neuronal necrosis, and CysLT2shRNA and HAMI3379inhibited the induced necrosis. Montelukast showed an inhibitory trend but no significant effect on OGD/R-and LTD4-induced necrosis, while CysLT1R siRNA had no effect.
These findings demonstrated that the CysLT2R, as the primary regulatory factor, might mediate microglial activation (enhancing phagocytosis and cytokine release), and thereby induce neuronal injury. CysLT1R might partially regulate cytokine release from microglia, and montelukast might inhibit neuronal injury through CysLT1R-dependent and independent mechanisms.
Conclusions:
1. In primary rat cortical neurons, CysLTs and their receptors do not directly mediate OGD/R-induced ischemic injury.
2. In the mixed cultures of rat cortical cells, CysLT1R, but not CysLT1R, mediates OGD/R-induced neuronal injury and microglial activation. In neuron-glial co-cultures, CysLT2R as the primary factor mediates OGD/R-induced neuronal injury via activating microglia, while CysLT1R partially regulates cytokine release from microglia; but the roles of CysLT receptors in astrocyte-mediated neuronal injury need investigation.
3. CysLT2R mediates OGD/R-induced microglial activation, and thereby induces neuronal injury via enhancing microglial phagocytosis and cytokine release. CysLT1R partially mediates neuronal injury via regulating cytokine release from microglia.
4. HAMI3379blocks CysLT2R-mediated responses, but montelukast exerts both CysLT1R-independent and dependent effects. Both of them may be potentially valuable for inhibition of inflammation after ischemic stroke.
引文
[1]KOSTANDY, B.B., The role of glutamate in neuronal ischemic injury:The role of spark in fire. Neurol Sci,2011.33(2):223-37.
[2]LAU, A. and TYMIANSKI, M., Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch,2010.460(2):525-42.
[3]CRACK, P.J. and TAYLOR, J.M., Reactive oxygen species and the modulation of stroke. Free Radic Biol Med,2005.38(11):1433-44.
[4]ALFADDA, A.A. and SALLAM, R.M., Reactive oxygen species in health and disease. J Biomed Biotechnol,2012.2012:936486.
[5]BANO, D. and NICOTERA, P., Ca2+signals and neuronal death in brain ischemia. Stroke, 2007.38(2 Suppl):674-6.
[6]WON, S.J., KIM, D.Y., and GWAG, B.J., Cellular and molecular pathways of ischemic neuronal death. J Biochem Mol Biol,2002.35(1):67-86.
[7]LOVE, S., Apoptosis and brain ischaemia. Prog Neuropsychopharmacol Biol Psychiatry,2003. 27(2):267-82.
[8]VILA, N., CASTILLO, J., DAVALOS, A., et al., Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke,2000.31(10):2325-9.
[9]CASTELLANOS, M., CASTILLO, J., GARCIA, M.M., et al., Inflammation-mediated damage in progressing lacunar infarctions:A potential therapeutic target Stroke,2002.33(4):982-7.
[10]SAIRANEN, T., RISTIMAKI, A., KARJALAINEN-LINDSBERG, M.L., et al., Cyclooxygenase-2 is induced globally in infarcted human brain. Ann Neurol,1998. 43(6):738-47.
[11]DORE, S., OTSUKA, T., MITO, T., et al., Neuronal overexpression of cyclooxygenase-2 increases cerebral infarction. Ann Neurol,2003.54(2):155-62.
[12]VIDENSKY, S., ZHANG, Y, HAND, T., et al., Neuronal overexpression of cox-2 results in dominant production of pge2 and altered fever response. Neuromolecular Med,2003. 3(1):15-28.
[13]EKDAHL, C.T., KOKAIA, Z., and LINDVALL, O., Brain inflammation and adult neurogenesis:The dual role of microglia. Neuroscience,2009.158(3):1021-9.
[14]RAMLACKHANSINGH, A.F., BROOKS, D.J., GREENWOOD, R.J., et al., Inflammation after trauma:Microglial activation and traumatic brain injury. Ann Neurol,2011.70(3):374-83.
[15]DE LEPELEIRE, I., REISS, T.F., ROCHETTE, F., et al., Montelukast causes prolonged, potent leukotriene d4-receptor antagonism in the airways of patients with asthma. Clin Pharmacol Ther,1997.61(1):83-92.
[16]SHIE, F.S. and WOLTJER, R.L., Manipulation of microglial activation as a therapeutic strategy in alzheimer's disease. Curr Med Chem,2007.14(27):2865-71.
[17]CRAIG, T.J., SHERKAT, A., and SAFAEE, S., Congestion and sleep impairment in allergic rhinitis. Curr Allergy Asthma Rep,2010.10(2):113-21.
[18]LI, F., ZHU, S., WU, C., et al., Neuroinflammation and cell therapy for parkinson's disease. Front Biosci (Schol Ed),2011.3:1407-20.
[19]FAWCETT, J.W. and ASHER, R.A., The glial scar and central nervous system repair. Brain Res Bull,1999.49(6):377-91.
[20]FITCH, M.T. and SILVER, J., Cns injury, glial scars, and inflammation:Inhibitory extracellular matrices and regeneration failure. Exp Neurol,2008.209(2):294-301.
[21]ROLLS, A., SHECHTER, R., and SCHWARTZ, M., The bright side of the glial scar in cns repair. Nat Rev Neurosci,2009.10(3):235-41.
[22]SOFRONIEW, M.V. and VINTERS, H.V., Astrocytes:Biology and pathology. Acta Neuropathol,2009.119(1):7-35.
[23]NAKAMACHI, T., FARKAS, J., WATANABE, J., et al., Role of pacap in neural stem/progenitor cell and astrocyte--from neural development to neural repair. Curr Pharm Des, 2011.17(10):973-84.
[24]SIU, D., Anew way of targeting to treat nerve injury. Int J Neurosci,2010.120(1):1-10.
[25]SINGH, R.K., GUPTA, S., DASTIDAR, S., et al., Cysteinyl leukotrienes and their receptors: Molecular and functional characteristics. Pharmacology,2010.85(6):336-49.
[26]CIANA, P., FUMAGALLI, M., TRINCAVELLI, M.L., et al., The orphan receptor gpr17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor. EMBO J,2006. 25(19):4615-27.
[27]BENNED-JENSEN, T. and ROSENKILDE, M.M., Distinct expression and ligand-binding profiles of two constitutively active gpr17 splice variants. Br J Pharmacol,2010. 159(5):1092-105.
[28]BACK, M., DAHLEN, S.E., DRAZEN, J.M., et al., International union of basic and clinical pharmacology. Lxxxiv:Leukotriene receptor nomenclature, distribution, and pathophysiological functions. Pharmacol Rev,2011.63(3):539-84.
[29]HUI, Y., CHENG, Y., SMALERA, I., et al., Directed vascular expression of human cysteinyl leukotriene 2 receptor modulates endothelial permeability and systemic blood pressure. Circulation,2004.110(21):3360-6.
[30]WOSZCZEK, G, CHEN, L.Y., NAGINENI, S., et al., Ifn-gamma induces cysteinyl leukotriene receptor 2 expression and enhances the responsiveness of human endothelial cells to cysteinyl leukotrienes. J Immunol,2007.178(8):5262-70.
[31]JIANG, W., HALL, S.R., MOOS, M.P., et al., Endothelial cysteinyl leukotriene 2 receptor expression mediates myocardial ischemia-reperfusion injury. Am J Pathol,2008. 172(3):592-602.
[32]MOOS, M.P., MEWBURN, J.D., KAN, F.W., et al., Cysteinyl leukotriene 2 receptor-mediated vascular permeability via transendothelial vesicle transport FASEB J,2008.22(12):4352-62.
[33]JIANG, Y, BORRELLI, L.A., KANAOKA, Y., et al., Cyslt2 receptors interact with cysltl receptors and down-modulate cysteinyl leukotriene dependent mitogenic responses of mast cells. Blood,2007.110(9):3263-70.
[34]BELLER, T.C., MAEKAWA, A., FRIEND, D.S., et al., Targeted gene disruption reveals the role of the cysteinyl leukotriene 2 receptor in increased vascular permeability and in bleomycin-induced pulmonary fibrosis in mice. J Biol Chem,2004.279(44):46129-34.
[35]MAGNUSSON, C., EHRNSTROM, R., OLSEN, J., et al., An increased expression of cysteinyl leukotriene 2 receptor in colorectal adenocarcinomas correlates with high differentiation. Cancer Res,2007.67(19):9190-8.
[36]MAGNUSSON, C., MEZHYBOVSKA, M., LORINC, E., et al., Low expression of cysltlr and high expression of cyslt2r mediate good prognosis in colorectal cancer. Eur J Cancer,2010. 46(4):826-35.
[37]MAGNUSSON, C., LIU, J., EHRNSTROM, R., et al., Cysteinyl leukotriene receptor expression pattern affects migration of breast cancer cells and survival of breast cancer patients. Int J Cancer,2011.129(1):9-22.
[38]KAMOHARA, M., TAKASAKI, J., MATSUMOTO, M., et al., Functional characterization of cysteinyl leukotriene cyslt(2) receptor on human coronary artery smooth muscle cells. Biochem Biophys Res Commun,2001.287(5):1088-92.
[39]HUANG, X.J., ZHANG, W.P., LI, C.T., et al., Activation of cyslt receptors induces astrocyte proliferation and death after oxygen-glucose deprivation. Glia,2008.56(1):27-37.
[40]ZHOU, Y, WEI, E.Q., FANG, S.H., et al., Spatio-temporal properties of 5-lipoxygenase expression and activation in the brain after focal cerebral ischemia in rats. Life Sci,2006. 79(17):1645-56.
[41]FANG, S.H., WEI, E.Q., ZHOU, Y, et al., Increased expression of cysteinyl leukotriene receptor-1 in the brain mediates neuronal damage and astrogliosis after focal cerebral ischemia in rats. Neuroscience,2006.140(3):969-79.
[42]FANG, S.H., ZHOU, Y., CHU, L.S., et al., Spatio-temporal expression of cysteinyl leukotriene receptor-2 mrna in rat brain after focal cerebral ischemia. Neurosci Lett,2007.412(1):78-83.
[43]ZHAO, C.Z., ZHAO, B., ZHANG, X.Y, et al., Cysteinyl leukotriene receptor 2 is spatiotemporally involved in neuron injury, astrocytosis and microgliosis after focal cerebral ischemia in rats. Neuroscience,2011.189:1-11.
[44]SHENG, W.W., LI, C.T., ZHANG, W.P., et al., Distinct roles of cysltl and cyslt2 receptors in oxygen glucose deprivation-induced pe12 cell death. Biochem Biophys Res Commun,2006. 346(1):19-25.
[45]HU, X., GE, Q.F., ZHANG, W.P., et al., [effects of cysteinyl receptor agonist and antagonists on rat primary cortical neurons]. Zhejiang Da Xue Xue Bao Yi Xue Ban,2007.36(2):117-22.
[46]WU, X., ZHOU, C., DU, F., et al., Ginkgolide b preconditioning on astrocytes promotes neuronal survival in ischemic injury via up-regulating erythropoietin secretion Neurochem Int, 2012.62(2):157-64.
[47]TRENDELENBURG, G. and DIRNAGL, U., Neuroprotective role of astrocytes in cerebral ischemia:Focus on ischemic preconditioning. Glia,2005.50(4):307-20.
[48]JACOBS, S. and DOERING, L.C., Astrocytes prevent abnormal neuronal development in the fragile x mouse. J Neurosci,2010.30(12):4508-14.
[49]QI, L.L., FANG, S.H., SHI, W.Z., et al., Cyslt2 receptor-mediated aqp4 up-regulation is involved in ischemic-like injury through activation of erk and p38 mapk in rat astrocytes. Life Sci,2011.88(l-2):50-6.
[50]WANG, M.L., HUANG, X.J., FANG, S.H., et al., Leukotriene d4 induces brain edema and enhances cyslt2 receptor-mediated aquaporin 4 expression. Biochem Biophys Res Commun, 2006.350(2):399-404.
[51]CHU, L.S., WEI, E.Q., YU, G.L., et al., Pranlukast reduces neutrophil but not macrophage/microglial accumulation in brain after focal cerebral ischemia in mice. Acta Pharmacol Sin,2006.27(3):282-8.
[52]ZHANG, W.P., WEI, E.Q., MEI, R.H., et al., Neuroprotective effect of ono-1078, a leukotriene receptor antagonist, on focal cerebral ischemia in rats. Acta Pharmacol Sin,2002.23(10):871-7.
[53]YU, GL., WEI, E.Q., WANG, M.L., et al., Pranlukast, a cysteinyl leukotriene receptor-1 antagonist, protects against chronic ischemic brain injury and inhibits the glial scar formation in mice. Brain Res,2005.1053(1-2):116-25.
[54]ZHAO, R., SHI, W.Z., ZHANG, Y.M., et al., Montelukast, a cysteinyl leukotriene receptor-1 antagonist, attenuates chronic brain injury after focal cerebral ischaemia in mice and rats. J Pharm Pharmacol,2011.63(4):550-7.
[55]WANG, X.X., ZHANG, X.Y., HUANG, X.Q., et al., [effect of montelukast on morphological changes in neurons after ischemic injury]. Zhejiang Da Xue Xue Bao Yi Xue Ban,2012. 41(3):259-66.
[56]YAN, D., STOCCO, R., SAWYER, N., et al., Differential signaling of cysteinyl leukotrienes and a novel cysteinyl leukotriene receptor 2 (cyslt(2)) agonist, n-methyl-leukotriene c(4), in calcium reporter and beta arrestin assays. Mol Pharmacol,2010.79(2):270-8.
[57]NI, N.C., YAN, D., BALLANTYNE, L.L., et al., A selective cysteinyl leukotriene receptor 2 antagonist blocks myocardial ischemia/reperfusion injury and vascular permeability in mice. J Pharmacol Exp Ther,2011.339(3):768-78.
[58]XU, L., ZHANG, L., LIU, L., et al., Involvement of cysteinyl leukotriene receptors in angiogenesis in rat thoracic aortic rings. Pharmazie,2010.65(10):750-4.
[59]WUNDER, F., TINEL, H., KAST, R., et al., Pharmacological characterization of the first potent and selective antagonist at the cysteinyl leukotriene 2 (cyslt(2)) receptor. Br J Pharmacol,2010. 160(2):399-409.
[60]SHI, Q.J., XIAO, L., ZHAO, B., et al., Intracerebroventricular injection of hami 3379, a selective cysteinyl leukotriene receptor 2 antagonist, protects against acute brain injury after focal cerebral ischemia in rats. Brain Res,2012.1484:57-67.
[61]MELONI, B.P., MAJDA, B.T., and KNUCKEY, N.W., Establishment of neuronal in vitro models of ischemia in 96-well microtiter strip-plates that result in acute, progressive and delayed neuronal death. Neuroscience,2001.108(1):17-26.
[62]MAEKAWA, A., BALESTRIERI, B., AUSTEN, K.F., et al., Gpr17 is a negative regulator of the cysteinyl leukotriene 1 receptor response to leukotriene d4. Proc Natl Acad Sci U S A,2009. 106(28):11685-90.
[63]IIJIMA, A., HACHISU, R., KOBAYASHI, H., et al., Establishment of evaluation method for sirna delivery using stable cell line carrying the luciferase reporter gene. Biol Pharm Bull,2007. 30(10):1844-50.
[64]DREYER, J.L., Lentiviral vector-mediated gene transfer and rna silencing technology in neuronal dysfunctions. Methods Mol Biol,2010.614:3-35.
[65]SCHERR, M., BATTMER, K., GANSER, A., et al., Modulation of gene expression by lentiviral-mediated delivery of small interfering rna. Cell Cycle,2003.2(3):251-7.
[66]GE, Q.F., HU, X., MA, Z.Q., et al., Baicalin attenuates oxygen-glucose deprivation-induced injury via inhibiting nmda receptor-mediated 5-lipoxygenase activation in rat cortical neurons. Pharmacol Res,2007.55(2):148-57.
[67]GE, Q.F., WEI, E.Q., ZHANG, W.P., et al., Activation of 5-lipoxygenase after oxygen-glucose deprivation is partly mediated via nmda receptor in rat cortical neurons. J Neurochem,2006. 97(4):992-1004.
[68]GOLDBERG, M.P. and CHOI, D.W., Combined oxygen and glucose deprivation in cortical cell culture:Calcium-dependent and calcium-independent mechanisms of neuronal injury. J Neurosci,1993.13(8):3510-24.
[69]HU, X., GE, Q.F., ZHANG, L., et al., [homeostatic conditions affect the protective effect of edaravone on ischemic injury in neurons]. Zhejiang Da Xue Xue Bao Yi Xue Ban,2006. 35(2):147-53.
[70]SONG, Y., WEI, E.Q., ZHANG, W.P., et al., Minocycline protects pc12 cells from ischemic-like injury and inhibits 5-lipoxygenase activation. Neuroreport,2004.15(14):2181-4.
[71]HANNON, G.J., Rna interference. Nature,2002.418(6894):244-51.
[72]SCHREIER, H., The new frontier:Gene and oligonucleotide therapy. Pharm Acta Helv,1994. 68(3):145-59.
[73]GRIMM, D. and KAY, M.A., Therapeutic application of rnai:Is mrna targeting finally ready for prime time? J Clin Invest,2007.117(12):3633-41.
[74]SUZUKI, R., TAKIZAWA, T, NEGISHI, Y, et al., Effective gene delivery with novel liposomal bubbles and ultrasonic destruction technology. Int J Pharm,2008.354(1-2):49-55.
[75]MORRIS, K.V. and ROSSI, J.J., Lentiviral-mediated delivery of sirnas for antiviral therapy. Gene Ther,2006.13(6):553-8.
[76]ZHAO, Z.Q., Postconditioning in reperfusion injury:A status report Cardiovasc Drugs Ther, 2010.24(3):265-79.
[77]NIIZUMA, K., YOSHIOKA, H., CHEN, H., et al., Mitochondrial and apoptotic neuronal death signaling pathways in cerebral ischemia. Biochim Biophys Acta,2009.1802(1):92-9.
[78]CHAN, P.H., Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab,2001.21(1):2-14.
[79]SENER, G., KABASAKAL, L., CETINEL, S., et al., Leukotriene receptor blocker montelukast protects against burn-induced oxidative injury of the skin and remote organs. Burns,2005. 31(5):587-96.
[80]TUGTEPE, H., SENER, G., CETINEL, S., et al., Oxidative renal damage in pyelonephritic rats is ameliorated by montelukast, a selective leukotriene cysltl receptor antagonist. Eur J Pharmacol,2007.557(1):69-75.
[81]KALONIA, H., KUMAR, P., KUMAR, A., et al., Protective effect of montelukast against quinolinic acid/malonic acid induced neurotoxicity:Possible behavioral, biochemical, mitochondrial and tumor necrosis factor-alpha level alterations in rats. Neuroscience,2010. 171(1):284-99.
[82]MUELLER, C.F., BECHER, M.U., ZIMMER, S., et al., Angiotensin ii triggers release of leukotriene c4 in vascular smooth muscle cells via the multidrug resistance-related protein 1. Mol Cell Biochem,2010.333(1-2):261-7.
[83]MOHAMADIN, A.M., ELBERRY, A.A., ELKABLAWY, M.A., et al., Montelukast, a leukotriene receptor antagonist abrogates lipopolysaccharide-induced toxicity and oxidative stress in rat liver. Pathophysiology,2011.18(3):235-42.
[84]BECHER, U.M., GHANEM, A., TIYERILI, V., et al., Inhibition of leukotriene c4 action reduces oxidative stress and apoptosis in cardiomyocytes and impedes remodeling after myocardial injury. J Mol Cell Cardiol,2011.50(3):570-7.
[85]COSKUN, A.K., YIGITER, M., ORAL, A., et al., The effects of montelukast on antioxidant enzymes and proinflammatory cytokines on the heart, liver, lungs, and kidneys in a rat model of cecal ligation and puncture-induced sepsis. ScientificWorldJournal,2011.11:1341-56.
[86]OFFER, S., SHOSEYOV, D., BIBI, H., et al., A leukotriene receptor antagonist modulates inos in the lung and in a leukotriene-free cell model. Nitric Oxide,2003.9(1):10-7.
[87]SILVA, R.C., LANDGRAF, M.A., HIYANE, M.I., et al., Leukotrienes produced in allergic lung inflammation activate alveolar macrophages. Cell Physiol Biochem,2010.26(3):319-26.
[88]KABASAKAL, L., SENER, G, CETINEL, S., et al., Burn-induced oxidative injury of the gut is ameliorated by the leukotriene receptor blocker montelukast. Prostaglandins Leukot Essent Fatty Acids,2005.72(6):431-40.
[89]DENGIZ, G.O., ODABASOGLU, F., HALICI, Z., et al., Gastroprotective and antioxidant effects of montelukast on indomethacin-induced gastric ulcer in rats. J Pharmacol Sci,2007. 105(1):94-102.
[90]ANDERSON, R., THERON, A.J., GRAVETT, C.M., et al., Montelukast inhibits neutrophil pro-inflammatory activity by a cyclic amp-dependent mechanism. Br J Pharmacol,2009. 156(1):105-15.
[91]MUTHURAMAN, A. and SOOD, S., Antisecretory, antioxidative and antiapoptotic effects of montelukast on pyloric ligation and water immersion stress induced peptic ulcer in rat. Prostaglandins Leukot Essent Fatty Acids,2010.83(1):55-60.
[92]LY, J.D., GRUBB, D.R., and LAWEN, A., The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis,2003.8(2):115-28.
[93]SUSIN, S.A., ZAMZAMI, N., and KROEMER, G, Mitochondria as regulators of apoptosis: Doubt no more. Biochim Biophys Acta,1998.1366(1-2):151-65.
[94]IIJIMA, T., MISHIMA, T., AKAGAWA, K., et al., Mitochondrial hyperpolarization after transient oxygen-glucose deprivation and subsequent apoptosis in cultured rat hippocampal neurons. Brain Res,2003.993(1-2):140-5.
[95]IIJIMA, T., MISHIMA, T., AKAGAWA, K., et al., Neuroprotective effect of propofol on necrosis and apoptosis following oxygen-glucose deprivation--relationship between mitochondrial membrane potential and mode of death. Brain Res,2006.1099(1):25-32.
[96]IIJIMA, T., MISHIMA, T, TOHYAMA, M., et al., Mitochondrial membrane potential and intracellular atp content after transient experimental ischemia in the cultured hippocampal neuron. Neurochem Int,2003.43(3):263-9.
[97]JIANG, Y., BORRELLI, L., BACSKAI, B.J., et al., P2y6 receptors require an intact cysteinyl leukotriene synthetic and signaling system to induce survival and activation of mast cells. J Immunol,2009.182(2):1129-37.
[98]MAMEDOVA, L., CAPRA, V., ACCOMAZZO, M.R., et al., Cysltl leukotriene receptor antagonists inhibit the effects of nucleotides acting at p2y receptors. Biochem Pharmacol,2005. 71(1-2):115-25.
[99]LANGLOIS, A., FERLAND, C., TREMBLAY, G.M., et al., Montelukast regulates eosinophil protease activity through a leukotriene-independent mechanism. J Allergy Clin Immunol,2006. 118(1):113-9.
[100]ROBINSON, A.J., KASHANIN, D., ODOWD, F., et al., Montelukast inhibition of resting and gm-csf-stimulated eosinophil adhesion to vcam-1 under flow conditions appears independent of cyslt(1)r antagonism. J Leukoc Biol,2008.83(6):1522-9.
[101]DI GENNARO, A., CARNINI, C., BUCCELLATI, C., et al., Cysteinyl-leukotrienes receptor activation in brain inflammatory reactions and cerebral edema formation:A role for transcellular biosynthesis of cysteinyl-leukotrienes. FASEB J,2004.18(7):842-4.
[102]BALLERINI, P., DI IORIO, P., CICCARELLI, R., et al., P2yl and cysteinyl leukotriene receptors mediate purine and cysteinyl leukotriene co-release in primary cultures of rat microglia Int J Immunopathol Pharmacol,2005.18(2):255-68.
[103]GIFFARD, R.G and SWANSON, R.A., Ischemia-induced programmed cell death in astrocytes. Glia,2005.50(4):299-306.
[104]ANDERSON, M.F., BLOMSTRAND, F., BLOMSTRAND, C., et al., Astrocytes and stroke: Networking for survival? Neurochem Res,2003.28(2):293-305.
[105]AYATA, C. and ROPPER, A.H., Ischaemic brain oedema. J Clin Neurosci,2002.9(2):113-24.
[106]GURER, G, GURSOY-OZDEMIR, Y., ERDEMLI, E., et al., Astrocytes are more resistant to focal cerebral ischemia than neurons and die by a delayed necrosis. Brain Pathol,2009. 19(4):630-41.
[107]WARD, S.A., RANSOM, P. A., BOOTH, P.L., et al., Characterization of ramified microglia in tissue culture:Pinocytosis and motility. J Neurosci Res,1991.29(1):13-28.
[108]GRAEBER, M.B. and STREIT, W.J., Microglia:Biology and pathology. Acta Neuropathol, 2009.119(1):89-105.
[109]STOLZING, A., WENGNER, A., and GRUNE, T., Degradation of oxidized extracellular proteins by microglia Arch Biochem Biophys,2002.400(2):171-9.
[110]NAPOLI, I. and NEUMANN, H., Microglial clearance function in health and disease. Neuroscience,2009.158(3):1030-8.
[111]CANDELARIO-JALIL, E., DE OLIVEIRA, A.C., GRAF, S., et al., Resveratrol potently reduces prostaglandin e2 production and free radical formation in lipopolysaccharide-activated primary rat microglia J Neuroinflammation,2007.4:25.
[112]NI, M. and ASCHNER, M., Neonatal rat primary microglia:Isolation, culturing, and selected applications. Curr Protoc Toxicol,2010. Chapter 12:Unit 12 17.
[113]HUANG, X.Q., ZHANG, X.Y., WANG, X.R., et al., Transforming growth factor betal-induced astrocyte migration is mediated in part by activating 5-lipoxygenase and cysteinyl leukotriene receptor 1. J Neuroinflammation,2012.9:145.
[114]KLEGERIS, A. and MCGEER, P.L., Toxicity of human monocytic thp-1 cells and microglia toward sh-sy5y neuroblastoma cells is reduced by inhibitors of 5-lipoxygenase and its activating protein flap. J Leukoc Biol,2003.73(3):369-78.
[115]BACK, M., Leukotriene signaling in atherosclerosis and ischemia. Cardiovasc Drugs Ther, 2009.23(1):41-8.
[116]PARHAMIFAR, L., SIME, W., YUDINA, Y., et al., Ligand-induced tyrosine phosphorylation of cysteinyl leukotriene receptor 1 triggers internalization and signaling in intestinal epithelial cells. PLoS One,2010.5(12):e14439.
[117]ICHIYAMA, T., KAJIMOTO, M., HASEGAWA, M., et al., Cysteinyl leukotrienes enhance tumour necrosis factor-alpha-induced matrix metalloproteinase-9 in human monocytes/macrophages. Clin Exp Allergy,2007.37(4):608-14.
[118]XIA, W., HAN, J., HUANG, G, et al., Inflammation in ischaemic brain injury:Current advances and future perspectives. Clin Exp Pharmacol Physiol,2010.37(2):253-8.
[119]WEINSTEIN, J.R., KOERNER, I.P., and MOLLER, T., Microglia in ischemic brain injury. Future Neurol,2010.5(2):227-246.
[120]CEULEMANS, A.G, ZGAVC, T., KOOIJMAN, R., et al., The dual role of the neuroinflammatory response after ischemic stroke:Modulatory effects of hypothermia. J Neuroinflammation,2010.7:74.
[121]THOMPSON, C, CLOUTIER, A., BOSSE, Y., et al., Signaling by the cysteinyl-leukotriene receptor 2. Involvement in chemokine gene transcription. J Biol Chem,2008.283(4):1974-84.
[1]GUO, M.F., YU, J.Z., and MA, C.G, Mechanisms related to neuron injury and death in cerebral hypoxic ischaemia. Folia Neuropathol,2011.49(2):78-87.
[2]LAU, A. and TYMIANSKI, M., Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch,2010.460(2):525-42.
[3]BRADLEY, S.R., MARINO, M.J., WITTMANN, M., et al., Activation of group ii metabotropic glutamate receptors inhibits synaptic excitation of the substantia nigra pars reticulata. J Neurosci,2000.20(9):3085-94.
[4]BREYSSE, N., BAUNEZ, C., SPOOREN, W., et al., Chronic but not acute treatment with a metabotropic glutamate 5 receptor antagonist reverses the akinetic deficits in a rat model of parkinsonism. J Neurosci,2002.22(13):5669-78.
[5]KIRSCHSTEIN, T., BAUER, M., MULLER, L., et al., Loss of metabotropic glutamate receptor-dependent long-term depression via downregulation of mglur5 after status epilepticus. J Neurosci,2007.27(29):7696-704.
[6]KAWAHARA, Y. and KWAK, S., Excitotoxicity and als:What is unique about the ampa receptors expressed on spinal motor neurons? Amyotroph Lateral Scler Other Motor Neuron Disord,2005.6(3):131-44.
[7]BROUNS, R. and DE DEYN, P.P., The complexity of neurobiological processes in acute ischemic stroke. Clin Neurol Neurosurg,2009. 111(6):483-95.
[8]BOBIK, M., ELLISMAN, M.H., RUDY, B., et al., Potassium channel subunit kv3.2 and the water channel aquaporin-4 are selectively localized to cerebellar pinceau. Brain Res,2004. 1026(2):168-78.
[9]KOFUJI, P. and NEWMAN, E.A., Potassium buffering in the central nervous system. Neuroscience,2004.129(4):1045-56.
[10]LIANG, D., DAWSON, T.M., and DAWSON, V.L., What have genetically engineered mice taught us about ischemic injury? Curr Mol Med,2004.4(2):207-25.
[11]LOVE, S., Apoptosis and brain ischaemia. Prog Neuropsychopharmacol Biol Psychiatry,2003. 27(2):267-82.
[12]HARE, W.A. and WHEELER, L., Experimental glutamatergic excitotoxicity in rabbit retinal ganglion cells:Block by memantine. Invest Ophthalmol Vis Sci,2009.50(6):2940-8.
[13]SATTLER, R., XIONG, Z., LU, W.Y., et al., Specific coupling of nmda receptor activation to nitric oxide neurotoxicity by psd-95 protein. Science,1999.284(5421):1845-8.
[14]MEHTA, S.L., MANHAS, N., and RAGHUBIR, R., Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev,2007.54(1):34-66.
[15]CHANG, P.K., VERBICH, D., and MCKINNEY, R.A., Ampa receptors as drug targets in neurological disease-advantages, caveats, and future outlook. Eur J Neurosci,2012. 35(12):1908-16.
[16]PALMER, C.L., COTTON, L., and HENLEY, J.M., The molecular pharmacology and cell biology of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Pharmacol Rev,2005.57(2):253-77.
[17]KWAK, S. and KAWAHARA, Y., Deficient rna editing of glur2 and neuronal death in amyotropic lateral sclerosis. J Mol Med (Berl),2005.83(2):110-20.
[18]PELLEGRINI-GIAMPIETRO, D.E., GORTER, J.A., BENNETT, M.V., et al., The glur2 (glur-b) hypothesis:Ca(2+)-permeable ampa receptors in neurological disorders. Trends Neurosci,1997.20(10):464-70.
[19]KWAK, S., HIDEYAMA, T, YAMASHITA, T., et al., Ampa receptor-mediated neuronal death in sporadic als. Neuropathology,2010.30(2):182-8.
[20]SOMMER, C. and KIESSLING, M., Ischemia and ischemic tolerance induction differentially regulate protein expression of glurl, glur2, and ampa receptor binding protein in the gerbil hippocampus:Glur2 (glur-b) reduction does not predict neuronal death. Stroke,2002. 33(4):1093-100.
[21]FRIEDMAN, L.K., AVALLONE, J.M., and MAGRYS, B., Maturational effects of single and multiple early-life seizures on ampa receptors in prepubescent hippocampus. Dev Neurosci, 2007.29(6):427-37.
[22]AARTS, M.M. and TYMIANSKI, M., Molecular mechanisms underlying specificity of excitotoxic signaling in neurons. Curr Mol Med,2004.4(2):137-47.
[23]AKINS, P.T. and ATKINSON, R.P., Glutamate ampa receptor antagonist treatment for ischaemic stroke. Curr Med Res Opin,2002.18 Suppl 2:s9-13.
[24]CRACK, P.J. and TAYLOR, J.M., Reactive oxygen species and the modulation of stroke. Free Radic Biol Med,2005.38(11):1433-44.
[25]KIMURA, H., GULES, I., MEGURO, T, et al., Cytotoxicity of cytokines in cerebral microvascular endothelial cell. Brain Res,2003.990(1-2):148-56.
[26]DIRNAGL, U., IADECOLA, C., and MOSKOWITZ, M.A., Pathobiology of ischaemic stroke: An integrated view. Trends Neurosci,1999.22(9):391-7.
[27]FRASER, P. A., The role of free radical generation in increasing cerebrovascular permeability. Free Radic Biol Med,2011.51(5):967-77.
[28]ALFADDA, A.A. and SALLAM, R.M., Reactive oxygen species in health and disease. J Biomed Biotechnol,2012.2012:936486.
[29]BRIEGER, K., SCHIAVONE, S., MILLER, F.J., JR., et al., Reactive oxygen species:From health to disease. Swiss Med Wkly,2012.142:w13659.
[30]NIIZUMA, K., YOSHIOKA, H., CHEN, H., et al., Mitochondrial and apoptotic neuronal death signaling pathways in cerebral ischemia. Biochim Biophys Acta,2009.1802(1):92-9.
[31]CHAN, P.H., Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab,2001.21(1):2-14.
[32]ZHAO, Z.Q., Postconditioning in reperfusion injury:A status report. Cardiovasc Drugs Ther, 2010.24(3):265-79.
[33]SAEED, S.A., SHAD, K.F., SALEEM, T., et al., Some new prospects in the understanding of the molecular basis of the pathogenesis of stroke. Exp Brain Res,2007.182(1):1-10.
[34]JUNG, J.E., KIM, G.S., CHEN, H., et al., Reperfusion and neurovascular dysfunction in stroke: From basic mechanisms to potential strategies for neuroprotection Mol Neurobiol,2010. 41(2-3):172-9.
[35]NAKKA, V.P., GUSAIN, A., MEHTA, S.L., et al., Molecular mechanisms of apoptosis in cerebral ischemia:Multiple neuroprotective opportunities. Mol Neurobiol,2008.37(1):7-38.
[36]KIEWERT, C., HARTMANN, J., STOLL, J., et al., Ngp1-01 is a brain-permeable dual blocker of neuronal voltage-and ligand-operated calcium channels. Neurochem Res,2006. 31(3):395-9.
[37]MATSUDA, T, ARAKAWA, N., TAKUMA, K., et al., Sea0400, a novel and selective inhibitor of the na+-ca2+exchanger, attenuates reperfusion injury in the in vitro and in vivo cerebral ischemic models. J Pharmacol Exp Ther,2001.298(1):249-56.
[38]RACAY, P., TATARKOVA, Z., CHOMOVA, M., et at,, Mitochondrial calcium transport and mitochondrial dysfunction after global brain ischemia in rat hippocampus. Neurochem Res, 2009.34(8):1469-78.
[39]BROOKES, P.S., YOON, Y., ROBOTHAM, J.L., et al., Calcium, atp, and ros:A mitochondrial love-hate triangle. Am J Physiol Cell Physiol,2004.287(4):C817-33.
[40]ICHAS, F. and MAZAT, J.P., From calcium signaling to cell death:Two conformations for the mitochondrial permeability transition pore. Switching from low-to high-conductance state. Biochim Biophys Acta,1998.1366(1-2):33-50.
[41]ROSENBERG, G.A., ESTRADA, E.Y., and DENCOFF, J.E., Matrix metalloproteinases and timps are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke, 1998,29(10):2189-95.
[42]GROENENDYK, J., LYNCH, J., and MICHALAK, M., Calreticulin, ca2+, and calcineurin-signaling from the endoplasmic reticulum. Mol Cells,2004.17(3):383-9.
[43]ZHANG, W., PETROVIC, J.M., CALLAGHAN, D., et al, Evidence that hypoxia-inducible factor-1 (hif-1) mediates transcriptional activation of interleukin-lbeta (il-1beta) in astrocyte cultures. J Neuroimmunol, 2006.174(1-2):63-73.
[44]FREDERICKSON, C.J., GIBLIN, L.J., KREZEL, A., et al., Concentrations of extracellular free zinc (pzn)e in the central nervous system during simple anesthetization, ischemia and reperfusion Exp Neurol,2006.198(2):285-93.
[45]KITAMURA, Y., IIDA, Y., ABE, J., et al., Release of vesicular zn2+in a rat transient middle cerebral artery occlusion model Brain Res Bull,2006.69(6):622-5.
[46]SENSI, S.L., PAOLETTI, P., BUSH, A.I., et at, Zinc in the physiology and pathology of the ens. Nat Rev Neurosci,2009.10(11):780-91.
[47]MARET, W., Metallothionein redox biology in the cytoprotective and cytotoxic functions of zinc. Exp Gerontol,2008.43(5):363-9.
[48]AIZENMAN, E., STOUT, A.K., HARTNETT, K.A., et al., Induction of neuronal apoptosis by thiol oxidation:Putative role of intracellular zinc release. J Neurochem,2000.75(5):1878-88.
[49]SENSI, S.L., TON-THAT, D., SULLIVAN, P.G, et al., Modulation of mitochondrial function by endogenous zn2+ pools. Proc Natl Acad Sci U S A,2003.100(10):6157-62.
[50]GAZARYAN, I.G., KRASINSKAYA, I.P., KRISTAL, B.S., et al., Zinc irreversibly damages major enzymes of energy production and antioxidant defense prior to mitochondrial permeability transition. J Biol Chem,2007.282(33):24373-80.
[51]WEISS, J.H., SENSI, S.L., and KOH, J.Y., Zn(2+):A novel ionic mediator of neural injury in brain disease. Trends Pharmacol Sci,2000.21(10):395-401.
[52]DINELEY, K.E., RICHARDS, L.L., VOTYAKOVA, T.V., et al., Zinc causes loss of membrane potential and elevates reactive oxygen species in rat brain mitochondria. Mitochondrion,2005. 5(1):55-65.
[53]JIANG, D., SULLIVAN, P.G, SENSI, S.L., et al., Zn(2+) induces permeability transition pore opening and release of pro-apoptotic peptides from neuronal mitochondria J Biol Chem,2001. 276(50):47524-9.
[54]KOH, J.Y., SUH, S.W., GWAG, B.J., et al., The role of zinc in selective neuronal death after transient global cerebral ischemia. Science,1996.272(5264):1013-6.
[55]SUH, S.W., CHEN, J.W., MOTAMEDI, M., et al., Evidence that synaptically-released zinc contributes to neuronal injury after traumatic brain injury. Brain Res,2000.852(2):268-73.
[56]MEDVEDEVA, Y.V., LIN, B., SHUTTLEWORTH, C.W., et al., Intracellular zn2+ accumulation contributes to synaptic failure, mitochondrial depolarization, and cell death in an acute slice oxygen-glucose deprivation model of ischemia J Neurosci,2009.29(4):1105-14.
[57]HONG, S.J., DAWSON, T.M., and DAWSON, V.L., Nuclear and mitochondrial conversations in cell death:Parp-1 and aif signaling. Trends Pharmacol Sci,2004.25(5):259-64.
[58]SUSIN, S.A., ZAMZAMI, N., and KROEMER, G, Mitochondria as regulators of apoptosis: Doubt no more. Biochim Biophys Acta,1998.1366(1-2):151-65.
[59]LY, J.D., GRUBB, D.R., and LAWEN, A., The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis,2003.8(2):115-28.
[60]BOUJRAD, H., GUBKINA, O., ROBERT, N., et al., Aif-mediated programmed necrosis:A highly regulated way to die. Cell Cycle,2007.6(21):2612-9.
[61]SOLAROGLU, I., TSUBOKAWA, T., CAHILL, J., et al., Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat Neuroscience, 2006.143(4):965-74.
[62]NAKAGAWA, T., ZHU, H., MORISHIMA, N., et al., Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta Nature,2000. 403(6765):98-103.
[63]RAO, R.V., HERMEL, E., CASTRO-OBREGON, S., et al., Coupling endoplasmic reticulum stress to the cell death program. Mechanism of caspase activation. J Biol Chem,2001. 276(36):33869-74.
[64]LIU, T, CLARK, R.K., MCDONNELL, P.C., et al., Tumor necrosis factor-alpha expression in ischemic neurons. Stroke,1994.25(7):1481-8.
[65]BUTTINI, M., APPEL, K., SAUTER, A., et al., Expression of tumor necrosis factor alpha after focal cerebral ischaemia in the rat Neuroscience,1996.71(1):1-16.
[66]WANG, X., YUE, T.L., BARONE, F.C., et al., Concomitant cortical expression of tnf-alpha and il-1 beta mrnas follows early response gene expression in transient focal ischemia. Mol Chem Neuropathol,1994.23(2-3):103-14.
[67]TOMIMOTO, H., AKIGUCHI, I., WAKITA, H., et al., Glial expression of cytokines in the brains of cerebrovascular disease patients. Acta Neuropathol,1996.92(3):281-7.
[68]SAIRANEN, T., CARPEN, O., KARJALAINEN-LINDSBERG, M.L., et al., Evolution of cerebral tumor necrosis factor-alpha production during human ischemic stroke. Stroke,2001. 32(8):1750-8.
[69]VILA, N., CASTILLO, J., DAVALOS, A., et al., Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke,2000.31(10):2325-9.
[70]ZAREMBA, J., SKROBANSKI, P., and LOSY, J., Tumour necrosis factor-alpha is increased in the cerebrospinal fluid and serum of ischaemic stroke patients and correlates with the volume of evolving brain infarct. Biomed Pharmacother,2001.55(5):258-63.
[71]CASTELLANOS, M., CASTILLO, J., GARCIA, M.M., et al., Inflammation-mediated damage in progressing lacunar infarctions:A potential therapeutic target Stroke,2002.33(4):982-7.
[72]YANG, G.Y., GONG, C., QIN, Z., et al., Inhibition of tnfalpha attenuates infarct volume and icam-1 expression in ischemic mouse brain. Neuroreport,1998.9(9):2131-4.
[73]LAVINE, S.D., HOFMAN, F.M., and ZLOKOVIC, B.V., Circulating antibody against tumor necrosis factor-alpha protects rat brain from reperfusion injury. J Cereb Blood Flow Metab, 1998.18(1):52-8.
[74]WANG, C.X. and SHUAIB, A., Involvement of inflammatory cytokines in central nervous system injury. Prog Neurobiol,2002.67(2):161-72.
[75]BARONE, F.C., ARVIN, B., WHITE, R.F., et al., Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury. Stroke,1997.28(6):1233-44.
[76]BRUCE, A.J., BOLING, W., KINDY, M.S., et al., Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking tnf receptors. Nat Med,1996. 2(7):788-94.
[77]ZOU, J.Y. and CREWS, F.T., Tnf alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures:Neuroprotection by nf kappa b inhibition. Brain Res,2005.1034(1-2):11-24.
[78]GINIS, I., JAISWAL, R., KLIMANIS, D., et al., Tnf-alpha-induced tolerance to ischemic injury involves differential control of nf-kappab transactivation:The role of nf-kappab association with p300 adaptor. J Cereb Blood Flow Metab,2002.22(2):142-52.
[79]PRADILLO, J.M., ROMERA, C., HURTADO, O., et al., Tnfrl upregulation mediates tolerance after brain ischemic preconditioning. J Cereb Blood Flow Metab,2005.25(2):193-203.
[80]PRADILLO, J.M., HURTADO, O., ROMERA, C., et al., Tnfrl mediates increased neuronal membrane eaat3 expression after in vivo cerebral ischemic preconditioning. Neuroscience, 2006.138(4):1171-8.
[81]DINARELLO, C.A., Interleukin-1 and interleukin-1 antagonism. Blood,1991.77(8):1627-52.
[82]DRIPPS, D.J., BRANDHUBER, B.J., THOMPSON, R.C., et al., Interleukin-1 (il-1) receptor antagonist binds to the 80-kda il-1 receptor but does not initiate il-1 signal transduction. J Biol Chem,1991.266(16):10331-6.
[83]KOGA, S., OGAWA, S., KUWABARA, K., et al., Synthesis and release of interleukin 1 by reoxygenated human mononuclear phagocytes. J Clin Invest,1992.90(3):1007-15.
[84]ROTHWELL, N.J., Functions and mechanisms of interleukin 1 in the brain. Trends Pharmacol Sci,1991.12(11):430-6.
[85]MINAMI, M., KURAISHI, Y., and SATOH, M., Effects of kainic acid on messenger rna levels of il-1 beta, il-6, tnf alpha and lif in the rat brain. Biochem Biophys Res Commun,1991. 176(2):593-8.
[86]BUTTINI, M. and BODDEKE, H., Peripheral lipopolysaccharide stimulation induces interleukin-1 beta messenger rna in rat brain microglial cells. Neuroscience,1995. 65(2):523-30.
[87]BUTTINI, M., SAUTER, A., and BODDEKE, H.W., Induction of interleukin-1 beta mrna after focal cerebral ischaemia in the rat. Brain Res Mol Brain Res,1994.23(1-2):126-34.
[88]HAQQANI, A.S., NESIC, M., PRESTON, E., et al., Characterization of vascular protein expression patterns in cerebral ischemia/reperfusion using laser capture microdissection and icat-nanolc-ms/ms. FASEB J,2005.19(13):1809-21.
[89]DAVIES, C.A., LODDICK, S.A., TOULMOND, S., et al., The progression and topographic distribution of interleukin-1 beta expression after permanent middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab,1999.19(1):87-98.
[90]YAMASAKI, Y., MATSUURA, N., SHOZUHARA, H., et al., Interleukin-1 as a pathogenetic mediator of ischemic brain damage in rats. Stroke,1995.26(4):676-80; discussion 681.
[91]RELTON, J.K., MARTIN, D., THOMPSON, R.C., et al., Peripheral administration of interleukin-1 receptor antagonist inhibits brain damage after focal cerebral ischemia in the rat. Exp Neurol,1996.138(2):206-13.
[92]YANG, G.Y., ZHAO, Y.J., DAVIDSON, B.L., et al., Overexpression of interleukin-1 receptor antagonist in the mouse brain reduces ischemic brain injury. Brain Res,1997.751(2):181-8.
[93]PINTEAUX, E., ROTHWELL, N. J., and BOUTIN, H., Neuroprotective actions of endogenous interleukin-1 receptor antagonist (il-lra) are mediated by glia Glia,2006.53(5):551-6.
[94]CARLSON, N.G, WIEGGEL, W.A., CHEN, J., et al., Inflammatory cytokines il-1 alpha, il-1 beta, il-6, and tnf-alpha impart neuroprotection to an excitotoxin through distinct pathways. J Immunol,1999.163(7):3963-8.
[95]STRIJBOS, P.J. and ROTHWELL, N.J., Interleukin-1 beta attenuates excitatory amino acid-induced neurodegeneration in vitro:Involvement of nerve growth factor. J Neurosci,1995. 15(5Pt 1):3468-74.
[96]CASTILLO, J. and RODRIGUEZ, I., Biochemical changes and inflammatory response as markers for brain ischaemia:Molecular markers of diagnostic utility and prognosis in human clinical practice. Cerebrovasc Dis,2004.17 Suppl 1:7-18.
[97]SMITH, C.J., EMSLEY, H.C., GAVIN, C.M., et al., Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome. BMC Neurol,2004.4:2.
[98]TARKOWSKI, E., ROSENGREN, L., BLOMSTRAND, C., et al., Intrathecal release of pro-and anti-inflammatory cytokines during stroke. Clin Exp Immunol,1997.110(3):492-9.
[99]SPERA, P.A., ELLISON, J.A., FEUERSTEIN, G.Z., et al.,11-10 reduces rat brain injury following focal stroke. Neurosci Lett,1998.251(3):189-92.
[100]OOBOSHI, H., IBAYASHI, S., SHICHITA, T., et al., Postischemic gene transfer of interleukin-10 protects against both focal and global brain ischemia. Circulation,2005. 111(7):913-9.
[101]VAN EXEL, E., GUSSEKLOO, J., DE CRAEN, A.J., et al., Inflammation and stroke:The leiden 85-plus study. Stroke,2002.33(4):1135-8.
[102]VILA, N., CASTILLO, J., DAVALOS, A., et al., Levels of anti-inflammatory cytokines and neurological worsening in acute ischemic stroke. Stroke,2003.34(3):671-5.
[103]KLEMPT, N.D., SIRIMANNE, E., GUNN, A.J., et al., Hypoxia-ischemia induces transforming growth factor beta 1 mrna in the infant rat brain. Brain Res Mol Brain Res,1992. 13(1-2):93-101.
[104]WIESSNER, C., GEHRMANN, J., LINDHOLM, D., et al., Expression of transforming growth factor-beta 1 and interleukin-1 beta mrna in rat brain following transient forebrain ischemia Acta Neuropathol,1993.86(5):439-46.
[105]PAL, G., VINCZE, C., RENNER, E., et al., Time course, distribution and cell types of induction of transforming growth factor betas following middle cerebral artery occlusion in the rat brain. PLoS One,2012.7(10):e46731.
[106]JOHNSTON, R.E., DILLON-CARTER, O., FREED, W.J., et al., Trophic factor secreting kidney cell lines:In vitro characterization and functional effects following transplantation in ischemic rats. Brain Res,2001.900(2):268-76.
[107]BENVENISTE, E.N., Cytokine actions in the central nervous system. Cytokine Growth Factor Rev,1998.9(3-4):259-75.
[108]GROSS, C.E., BEDNAR, M.M., HOWARD, D.B., et al., Transforming growth factor-beta 1 reduces infarct size after experimental cerebral ischemia in a rabbit model. Stroke,1993. 24(4):558-62.
[109]PANG, L., YE, W., CHE, X.M., et al., Reduction of inflammatory response in the mouse brain with adenoviral-mediated transforming growth factor-ssl expression. Stroke,2001. 32(2):544-52.
[110]MORI, E., DEL ZOPPO, G.J., CHAMBERS, J.D., et al., Inhibition of polymorphonuclear leukocyte adherence suppresses no-reflow after focal cerebral ischemia in baboons. Stroke, 1992.23(5):712-8.
[111]YU, G.L., WEI, E.Q., ZHANG, S.H., et al., Montelukast, a cysteinyl leukotriene receptor-1 antagonist, dose-and time-dependently protects against focal cerebral ischemia in mice. Pharmacology,2005.73(1):31-40.
[112]NIJBOER, C.H., HEIJNEN, C.J., GROENENDAAL, F., et al., A dual role of the nf-kappab pathway in neonatal hypoxic-ischemic brain damage. Stroke,2008.39(9):2578-86.
[113]COJOCARU, I.M., MUSUROI, C., IACOB, S., et al, Investigation of tnf-alpha, il-6, il-8 and of procalcitonin in patients with neurologic complications in sepsis. Rom J Intern Med.2003. 41(1):83-93.
[114]STEPHENSON, D., YIN, T., SMALSTIG, E.B., et al., Transcription factor nuclear factor-kappa b is activated in neurons after focal cerebral ischemia. J Cereb Blood Flow Metab,2000. 20(3):592-603.
[115]FABIAN, R.H., PEREZ-POLO, J.R., and KENT, T.A., A decoy oligonucleotide inhibiting nuclear factor-kappab binding to the iggkappab consensus site reduces cerebral injury and apoptosis in neonatal hypoxic-ischemic encephalopathy. J Neurosci Res,2007.85(7):1420-6.
[116]SCHWAB, J.M., NGUYEN, T.D., POSTLER, E., et al., Selective accumulation of cyclooxygenase-1-expressing microglial cells/macrophages in lesions of human focal cerebral ischemia Acta Neuropathol,2000.99(6):609-14.
[117]IADECOLA, C, SUGIMOTO, K., NIWA, K., et al., Increased susceptibility to ischemic brain injury in cyclooxygenase-1-deficient mice. J Cereb Blood Flow Metab,2001.21(12):1436-41.
[118]CANDELARIO-JALIL, E., GONZALEZ-FALCON, A., GARCIA-CABRERA, M., et al., Assessment of the relative contribution of cox-1 and cox-2 isoforms to ischemia-induced oxidative damage and neurodegeneration following transient global cerebral ischemia. J Neurochem,2003.86(3):545-55.
[119]NOGAWA, S., ZHANG, F., ROSS, M.E., et al., Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. J Neurosci,1997.17(8):2746-55.
[120]KINOUCHI, H., HUANG, H., ARAI, S., et al., Induction of cyclooxygenase-2 messenger rna after transient and permanent middle cerebral artery occlusion in rats:Comparison with c-fos messenger rna by using in situ hybridization. J Neurosurg,1999.91(6):1005-12.
[121]PLANAS, A.M., SORIANO, M.A., RODRIGUEZ-FARRE, E., et al., Induction of cyclooxygenase-2 mrna and protein following transient focal ischemia in the rat brain. Neurosci Lett,1995.200(3):187-90.
[122]SAIRANEN, T., RISTIMAKI, A., KARJALAINEN-LINDSBERG, M.L.. et al., Cyclooxygenase-2 is induced globally in infarcted human brain. Ann Neurol,1998. 43(6):738-47.
[123]SUGIMOTO, K. and IADECOLA, C., Delayed effect of administration of cox-2 inhibitor in mice with acute cerebral ischemia Brain Res,2003.960(1-2):273-6.
[124]DORE, S., OTSUKA, T., MITO, T., et al., Neuronal overexpression of cyclooxygenase-2 increases cerebral infarction. Ann Neurol,2003.54(2):155-62.
[125]FUNK, C.D., Prostaglandins and leukotrienes:Advances in eicosanoid biology. Science,2001. 294(5548):1871-5.
[126]MONTUSCHI, P. and PETERS-GOLDEN, M.L., Leukotriene modifiers for asthma treatment. Clin Exp Allergy,2010.40(12):1732-41.
[127]PETERS-GOLDEN, M., GLEASON, M.M., and TOGIAS, A., Cysteinyl leukotrienes: Multi-functional mediators in allergic rhinitis. Clin Exp Allergy,2006.36(6):689-703.
[128]BLACK, K.L., HOFF, J.T., MCGILLICUDDY, J.E., et al., Increased leukotriene c4 and vasogenic edema surrounding brain tumors in humans. Ann Neurol,1986.19(6):592-5.
[129]FREIBERG, J.J., DAHL, M., TYBJAERG-HANSEN, A., et al., Leukotriene c4 synthase and ischemic cardiovascular disease and obstructive pulmonary disease in 13,000 individuals. J Mol Cell Cardiol,2009.46(4):579-86.
[130]CICERI, P., RABUFFETTI, M., MONOPOLI, A., et al., Production of leukotrienes in a model of focal cerebral ischaemia in the rat Br J Pharmacol,2001.133(8):1323-9.
[131]DHILLON, H.S., DOSE, J.M., and PRASAD, M.R., Regional generation of leukotriene c4 after experimental brain injury in anesthetized rats. J Neurotrauma,1996.13(12):781-9.
[132]SINGH, R.K., GUPTA, S., DASTIDAR, S., et al., Cysteinyl leukotrienes and their receptors: Molecular and functional characteristics. Pharmacology,2010.85(6):336-49.
[133]KANAOKA, Y. and BOYCE, J.A., Cysteinyl leukotrienes and their receptors:Cellular distribution and function in immune and inflammatory responses. J Immunol,2004. 173(3):1503-10.
[134]KILFEATHER, S.,5-lipoxygenase inhibitors for the treatment of copd. Chest,2002.121(5 Suppl):197S-200S.
[135]MEHRABIAN, M., ALLAYEE, H., WONG, J., et al., Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ Res,2002.91(2):120-6.
[136]STANKE-LABESQUE, F., HARDY, G, VERGNAUD, S., et al., Involvement of cysteinyl leukotrienes in angiotensin ii-induced contraction in isolated aortas from transgenic (mren-2)27 rats. J Hypertens,2002.20(2):263-72.
[137]WELT, K., FITZL, G, and MARK, B., Lipoxygenase inhibitor flm 5011, an effective protectant of myocardial microvessels against ischemia-reperfusion injury? An ultrastructural-morphometric study. Exp Toxicol Pathol,2000.52(1):27-36.
[138]HENNIG, R., DING, X.Z., TONG, W.G., et al.,5-lipoxygenase and leukotriene b(4) receptor are expressed in human pancreatic cancers but not in pancreatic ducts in normal tissue. Am J Pathol, 2002.161(2):421-8.
[139]SEUFFERLEIN, T., SECKL, M.J., SCHWARZ, E., et al., Mechanisms of nordihydroguaiaretic acid-induced growth inhibition and apoptosis in human cancer cells. Br J Cancer,2002. 86(7):1188-96.
[140]DAGLAR, GO., KAMA, N.A., ATLI, M., et al., Effect of 5-lipoxygenase inhibition on kupffer cell clearance capacity in obstructive jaundiced rats. J Surg Res,2001.96(2):158-62.
[141]MACCARRONE, M., TACCONE-GALLUCCI, M., MELONI, C, et al., Activation of 5-lipoxygenase and related cell membrane lipoperoxidation in hemodialysis patients. J Am Soc Nephrol,1999.10(9):1991-6.
[142]GOULET, J.L., GRIFFITHS, R.C., RUIZ, P., et al., Deficiency of 5-lipoxygenase accelerates renal allograft rejection in mice. J Immunol,2001.167(11):6631-6.
[143]BUTTERLY, D.W., SPURNEY, R.F., RUIZ, P., et al., A role for leukotrienes in cyclosporine nephrotoxicity. Kidney Int,2000.57(6):2586-93.
[144]TOMIMOTO, H., SHIBATA, M., IHARA, M., et al., A comparative study on the expression of cyclooxygenase and 5-lipoxygenase during cerebral ischemia in humans. Acta Neuropathol, 2002.104(6):601-7.
[145]CHU, L.S., WEI, E.Q., YU, GL., et al., Pranlukast reduces neutrophil but not macrophage/microglial accumulation in brain after focal cerebral ischemia in mice. Acta Pharmacol Sin,2006.27(3):282-8.
[146]ZHAO, C.Z., ZHAO, B., ZHANG, X.Y., et al., Cysteinyl leukotriene receptor 2 is spatiotemporally involved in neuron injury, astrocytosis and microgliosis after focal cerebral ischemia in rats. Neuroscience,2011.189:1-11.
[147]SHI, Q.J., XIAO, L., ZHAO, B., et al., Intracerebroventricular injection of hami 3379, a selective cysteinyl leukotriene receptor 2 antagonist, protects against acute brain injury after focal cerebral ischemia in rats. Brain Res,2012.1484:57-67.
[148]WINKING, M., DEINSBERGER, W., JOEDICKE, A., et al., Cysteinyl-leukotriene levels in intracerebral hemorrhage:An edema-promoting factor? Cerebrovasc Dis,1998.8(6):318-26.
[149]QI, L.L., FANG, S.H., SHI, W.Z., et al., Cyslt2 receptor-mediated aqp4 up-regulation is involved in ischemic-like injury through activation of erk and p38 mapk in rat astrocytes. Life Sci,2010.88(1-2):50-6.
[150]WANG, M.L., HUANG, X.J., FANG, S.H., et al., Leukotriene d4 induces brain edema and enhances cyslt2 receptor-mediated aquaporin 4 expression. Biochem Biophys Res Commun, 2006.350(2):399-404.
[151]OHTSUKI, T., MATSUMOTO, M., HAYASHI, Y., et al., Reperfusion induces 5-lipoxygenase translocation and leukotriene c4 production in ischemic brain. Am J Physiol,1995.268(3 Pt 2):H1249-57.
[152]RAO, A.M., HATCHER, J.F., KINDY, M.S., et al., Arachidonic acid and leukotriene c4:Role in transient cerebral ischemia of gerbils. Neurochem Res,1999.24(10):1225-32.
[153]BARBOSA, M.D., ARTHUR, A.S., LOUIS, R.H., et al., The novel 5-lipoxygenase inhibitor abt-761 attenuates cerebral vasospasm in a rabbit model of subarachnoid hemorrhage. Neurosurgery,2001.49(5):1205-12; discussion 1212-3.
[154]SHISHIDO, Y, FURUSHIRO, M., HASHIMOTO, S., et al., Effect of nordihydroguaiaretic acid on behavioral impairment and neuronal cell death after forebrain ischemia Pharmacol Biochem Behav,2001.69(3-4):469-74.
[155]ZHAO, R., SHI, W.Z., ZHANG, Y.M., et al., Montelukast, a cysteinyl leukotriene receptor-1 antagonist, attenuates chronic brain injury after focal cerebral ischaemia in mice and rats. J Pharm Pharmacol,2011.63(4):550-7.
[156]ZHANG, W.P., WEI, E.Q., MEI, R.H., et al., Neuroprotective effect of ono-1078, a leukotriene receptor antagonist, on focal cerebral ischemia in rats. Acta Pharmacol Sin,2002.23(10):871-7.
[157]YU, G.L., WEI, E.Q., WANG, M.L., et al., Pranlukast, a cysteinyl leukotriene receptor-1 antagonist, protects against chronic ischemic brain injury and inhibits the glial scar formation in mice. Brain Res,2005.1053(1-2):116-25.
[2]LAU, A. and TYMIANSKI, M., Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch,2010.460(2):525-42.
[3]CRACK, P.J. and TAYLOR, J.M., Reactive oxygen species and the modulation of stroke. Free Radic Biol Med,2005.38(11):1433-44.
[4]ALFADDA, A.A. and SALLAM, R.M., Reactive oxygen species in health and disease. J Biomed Biotechnol,2012.2012:936486.
[5]BANO, D. and NICOTERA, P., Ca2+signals and neuronal death in brain ischemia. Stroke, 2007.38(2 Suppl):674-6.
[6]WON, S.J., KIM, D.Y., and GWAG, B.J., Cellular and molecular pathways of ischemic neuronal death. J Biochem Mol Biol,2002.35(1):67-86.
[7]LOVE, S., Apoptosis and brain ischaemia. Prog Neuropsychopharmacol Biol Psychiatry,2003. 27(2):267-82.
[8]VILA, N., CASTILLO, J., DAVALOS, A., et al., Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke,2000.31(10):2325-9.
[9]CASTELLANOS, M., CASTILLO, J., GARCIA, M.M., et al., Inflammation-mediated damage in progressing lacunar infarctions:A potential therapeutic target Stroke,2002.33(4):982-7.
[10]SAIRANEN, T., RISTIMAKI, A., KARJALAINEN-LINDSBERG, M.L., et al., Cyclooxygenase-2 is induced globally in infarcted human brain. Ann Neurol,1998. 43(6):738-47.
[11]DORE, S., OTSUKA, T., MITO, T., et al., Neuronal overexpression of cyclooxygenase-2 increases cerebral infarction. Ann Neurol,2003.54(2):155-62.
[12]VIDENSKY, S., ZHANG, Y, HAND, T., et al., Neuronal overexpression of cox-2 results in dominant production of pge2 and altered fever response. Neuromolecular Med,2003. 3(1):15-28.
[13]EKDAHL, C.T., KOKAIA, Z., and LINDVALL, O., Brain inflammation and adult neurogenesis:The dual role of microglia. Neuroscience,2009.158(3):1021-9.
[14]RAMLACKHANSINGH, A.F., BROOKS, D.J., GREENWOOD, R.J., et al., Inflammation after trauma:Microglial activation and traumatic brain injury. Ann Neurol,2011.70(3):374-83.
[15]DE LEPELEIRE, I., REISS, T.F., ROCHETTE, F., et al., Montelukast causes prolonged, potent leukotriene d4-receptor antagonism in the airways of patients with asthma. Clin Pharmacol Ther,1997.61(1):83-92.
[16]SHIE, F.S. and WOLTJER, R.L., Manipulation of microglial activation as a therapeutic strategy in alzheimer's disease. Curr Med Chem,2007.14(27):2865-71.
[17]CRAIG, T.J., SHERKAT, A., and SAFAEE, S., Congestion and sleep impairment in allergic rhinitis. Curr Allergy Asthma Rep,2010.10(2):113-21.
[18]LI, F., ZHU, S., WU, C., et al., Neuroinflammation and cell therapy for parkinson's disease. Front Biosci (Schol Ed),2011.3:1407-20.
[19]FAWCETT, J.W. and ASHER, R.A., The glial scar and central nervous system repair. Brain Res Bull,1999.49(6):377-91.
[20]FITCH, M.T. and SILVER, J., Cns injury, glial scars, and inflammation:Inhibitory extracellular matrices and regeneration failure. Exp Neurol,2008.209(2):294-301.
[21]ROLLS, A., SHECHTER, R., and SCHWARTZ, M., The bright side of the glial scar in cns repair. Nat Rev Neurosci,2009.10(3):235-41.
[22]SOFRONIEW, M.V. and VINTERS, H.V., Astrocytes:Biology and pathology. Acta Neuropathol,2009.119(1):7-35.
[23]NAKAMACHI, T., FARKAS, J., WATANABE, J., et al., Role of pacap in neural stem/progenitor cell and astrocyte--from neural development to neural repair. Curr Pharm Des, 2011.17(10):973-84.
[24]SIU, D., Anew way of targeting to treat nerve injury. Int J Neurosci,2010.120(1):1-10.
[25]SINGH, R.K., GUPTA, S., DASTIDAR, S., et al., Cysteinyl leukotrienes and their receptors: Molecular and functional characteristics. Pharmacology,2010.85(6):336-49.
[26]CIANA, P., FUMAGALLI, M., TRINCAVELLI, M.L., et al., The orphan receptor gpr17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor. EMBO J,2006. 25(19):4615-27.
[27]BENNED-JENSEN, T. and ROSENKILDE, M.M., Distinct expression and ligand-binding profiles of two constitutively active gpr17 splice variants. Br J Pharmacol,2010. 159(5):1092-105.
[28]BACK, M., DAHLEN, S.E., DRAZEN, J.M., et al., International union of basic and clinical pharmacology. Lxxxiv:Leukotriene receptor nomenclature, distribution, and pathophysiological functions. Pharmacol Rev,2011.63(3):539-84.
[29]HUI, Y., CHENG, Y., SMALERA, I., et al., Directed vascular expression of human cysteinyl leukotriene 2 receptor modulates endothelial permeability and systemic blood pressure. Circulation,2004.110(21):3360-6.
[30]WOSZCZEK, G, CHEN, L.Y., NAGINENI, S., et al., Ifn-gamma induces cysteinyl leukotriene receptor 2 expression and enhances the responsiveness of human endothelial cells to cysteinyl leukotrienes. J Immunol,2007.178(8):5262-70.
[31]JIANG, W., HALL, S.R., MOOS, M.P., et al., Endothelial cysteinyl leukotriene 2 receptor expression mediates myocardial ischemia-reperfusion injury. Am J Pathol,2008. 172(3):592-602.
[32]MOOS, M.P., MEWBURN, J.D., KAN, F.W., et al., Cysteinyl leukotriene 2 receptor-mediated vascular permeability via transendothelial vesicle transport FASEB J,2008.22(12):4352-62.
[33]JIANG, Y, BORRELLI, L.A., KANAOKA, Y., et al., Cyslt2 receptors interact with cysltl receptors and down-modulate cysteinyl leukotriene dependent mitogenic responses of mast cells. Blood,2007.110(9):3263-70.
[34]BELLER, T.C., MAEKAWA, A., FRIEND, D.S., et al., Targeted gene disruption reveals the role of the cysteinyl leukotriene 2 receptor in increased vascular permeability and in bleomycin-induced pulmonary fibrosis in mice. J Biol Chem,2004.279(44):46129-34.
[35]MAGNUSSON, C., EHRNSTROM, R., OLSEN, J., et al., An increased expression of cysteinyl leukotriene 2 receptor in colorectal adenocarcinomas correlates with high differentiation. Cancer Res,2007.67(19):9190-8.
[36]MAGNUSSON, C., MEZHYBOVSKA, M., LORINC, E., et al., Low expression of cysltlr and high expression of cyslt2r mediate good prognosis in colorectal cancer. Eur J Cancer,2010. 46(4):826-35.
[37]MAGNUSSON, C., LIU, J., EHRNSTROM, R., et al., Cysteinyl leukotriene receptor expression pattern affects migration of breast cancer cells and survival of breast cancer patients. Int J Cancer,2011.129(1):9-22.
[38]KAMOHARA, M., TAKASAKI, J., MATSUMOTO, M., et al., Functional characterization of cysteinyl leukotriene cyslt(2) receptor on human coronary artery smooth muscle cells. Biochem Biophys Res Commun,2001.287(5):1088-92.
[39]HUANG, X.J., ZHANG, W.P., LI, C.T., et al., Activation of cyslt receptors induces astrocyte proliferation and death after oxygen-glucose deprivation. Glia,2008.56(1):27-37.
[40]ZHOU, Y, WEI, E.Q., FANG, S.H., et al., Spatio-temporal properties of 5-lipoxygenase expression and activation in the brain after focal cerebral ischemia in rats. Life Sci,2006. 79(17):1645-56.
[41]FANG, S.H., WEI, E.Q., ZHOU, Y, et al., Increased expression of cysteinyl leukotriene receptor-1 in the brain mediates neuronal damage and astrogliosis after focal cerebral ischemia in rats. Neuroscience,2006.140(3):969-79.
[42]FANG, S.H., ZHOU, Y., CHU, L.S., et al., Spatio-temporal expression of cysteinyl leukotriene receptor-2 mrna in rat brain after focal cerebral ischemia. Neurosci Lett,2007.412(1):78-83.
[43]ZHAO, C.Z., ZHAO, B., ZHANG, X.Y, et al., Cysteinyl leukotriene receptor 2 is spatiotemporally involved in neuron injury, astrocytosis and microgliosis after focal cerebral ischemia in rats. Neuroscience,2011.189:1-11.
[44]SHENG, W.W., LI, C.T., ZHANG, W.P., et al., Distinct roles of cysltl and cyslt2 receptors in oxygen glucose deprivation-induced pe12 cell death. Biochem Biophys Res Commun,2006. 346(1):19-25.
[45]HU, X., GE, Q.F., ZHANG, W.P., et al., [effects of cysteinyl receptor agonist and antagonists on rat primary cortical neurons]. Zhejiang Da Xue Xue Bao Yi Xue Ban,2007.36(2):117-22.
[46]WU, X., ZHOU, C., DU, F., et al., Ginkgolide b preconditioning on astrocytes promotes neuronal survival in ischemic injury via up-regulating erythropoietin secretion Neurochem Int, 2012.62(2):157-64.
[47]TRENDELENBURG, G. and DIRNAGL, U., Neuroprotective role of astrocytes in cerebral ischemia:Focus on ischemic preconditioning. Glia,2005.50(4):307-20.
[48]JACOBS, S. and DOERING, L.C., Astrocytes prevent abnormal neuronal development in the fragile x mouse. J Neurosci,2010.30(12):4508-14.
[49]QI, L.L., FANG, S.H., SHI, W.Z., et al., Cyslt2 receptor-mediated aqp4 up-regulation is involved in ischemic-like injury through activation of erk and p38 mapk in rat astrocytes. Life Sci,2011.88(l-2):50-6.
[50]WANG, M.L., HUANG, X.J., FANG, S.H., et al., Leukotriene d4 induces brain edema and enhances cyslt2 receptor-mediated aquaporin 4 expression. Biochem Biophys Res Commun, 2006.350(2):399-404.
[51]CHU, L.S., WEI, E.Q., YU, G.L., et al., Pranlukast reduces neutrophil but not macrophage/microglial accumulation in brain after focal cerebral ischemia in mice. Acta Pharmacol Sin,2006.27(3):282-8.
[52]ZHANG, W.P., WEI, E.Q., MEI, R.H., et al., Neuroprotective effect of ono-1078, a leukotriene receptor antagonist, on focal cerebral ischemia in rats. Acta Pharmacol Sin,2002.23(10):871-7.
[53]YU, GL., WEI, E.Q., WANG, M.L., et al., Pranlukast, a cysteinyl leukotriene receptor-1 antagonist, protects against chronic ischemic brain injury and inhibits the glial scar formation in mice. Brain Res,2005.1053(1-2):116-25.
[54]ZHAO, R., SHI, W.Z., ZHANG, Y.M., et al., Montelukast, a cysteinyl leukotriene receptor-1 antagonist, attenuates chronic brain injury after focal cerebral ischaemia in mice and rats. J Pharm Pharmacol,2011.63(4):550-7.
[55]WANG, X.X., ZHANG, X.Y., HUANG, X.Q., et al., [effect of montelukast on morphological changes in neurons after ischemic injury]. Zhejiang Da Xue Xue Bao Yi Xue Ban,2012. 41(3):259-66.
[56]YAN, D., STOCCO, R., SAWYER, N., et al., Differential signaling of cysteinyl leukotrienes and a novel cysteinyl leukotriene receptor 2 (cyslt(2)) agonist, n-methyl-leukotriene c(4), in calcium reporter and beta arrestin assays. Mol Pharmacol,2010.79(2):270-8.
[57]NI, N.C., YAN, D., BALLANTYNE, L.L., et al., A selective cysteinyl leukotriene receptor 2 antagonist blocks myocardial ischemia/reperfusion injury and vascular permeability in mice. J Pharmacol Exp Ther,2011.339(3):768-78.
[58]XU, L., ZHANG, L., LIU, L., et al., Involvement of cysteinyl leukotriene receptors in angiogenesis in rat thoracic aortic rings. Pharmazie,2010.65(10):750-4.
[59]WUNDER, F., TINEL, H., KAST, R., et al., Pharmacological characterization of the first potent and selective antagonist at the cysteinyl leukotriene 2 (cyslt(2)) receptor. Br J Pharmacol,2010. 160(2):399-409.
[60]SHI, Q.J., XIAO, L., ZHAO, B., et al., Intracerebroventricular injection of hami 3379, a selective cysteinyl leukotriene receptor 2 antagonist, protects against acute brain injury after focal cerebral ischemia in rats. Brain Res,2012.1484:57-67.
[61]MELONI, B.P., MAJDA, B.T., and KNUCKEY, N.W., Establishment of neuronal in vitro models of ischemia in 96-well microtiter strip-plates that result in acute, progressive and delayed neuronal death. Neuroscience,2001.108(1):17-26.
[62]MAEKAWA, A., BALESTRIERI, B., AUSTEN, K.F., et al., Gpr17 is a negative regulator of the cysteinyl leukotriene 1 receptor response to leukotriene d4. Proc Natl Acad Sci U S A,2009. 106(28):11685-90.
[63]IIJIMA, A., HACHISU, R., KOBAYASHI, H., et al., Establishment of evaluation method for sirna delivery using stable cell line carrying the luciferase reporter gene. Biol Pharm Bull,2007. 30(10):1844-50.
[64]DREYER, J.L., Lentiviral vector-mediated gene transfer and rna silencing technology in neuronal dysfunctions. Methods Mol Biol,2010.614:3-35.
[65]SCHERR, M., BATTMER, K., GANSER, A., et al., Modulation of gene expression by lentiviral-mediated delivery of small interfering rna. Cell Cycle,2003.2(3):251-7.
[66]GE, Q.F., HU, X., MA, Z.Q., et al., Baicalin attenuates oxygen-glucose deprivation-induced injury via inhibiting nmda receptor-mediated 5-lipoxygenase activation in rat cortical neurons. Pharmacol Res,2007.55(2):148-57.
[67]GE, Q.F., WEI, E.Q., ZHANG, W.P., et al., Activation of 5-lipoxygenase after oxygen-glucose deprivation is partly mediated via nmda receptor in rat cortical neurons. J Neurochem,2006. 97(4):992-1004.
[68]GOLDBERG, M.P. and CHOI, D.W., Combined oxygen and glucose deprivation in cortical cell culture:Calcium-dependent and calcium-independent mechanisms of neuronal injury. J Neurosci,1993.13(8):3510-24.
[69]HU, X., GE, Q.F., ZHANG, L., et al., [homeostatic conditions affect the protective effect of edaravone on ischemic injury in neurons]. Zhejiang Da Xue Xue Bao Yi Xue Ban,2006. 35(2):147-53.
[70]SONG, Y., WEI, E.Q., ZHANG, W.P., et al., Minocycline protects pc12 cells from ischemic-like injury and inhibits 5-lipoxygenase activation. Neuroreport,2004.15(14):2181-4.
[71]HANNON, G.J., Rna interference. Nature,2002.418(6894):244-51.
[72]SCHREIER, H., The new frontier:Gene and oligonucleotide therapy. Pharm Acta Helv,1994. 68(3):145-59.
[73]GRIMM, D. and KAY, M.A., Therapeutic application of rnai:Is mrna targeting finally ready for prime time? J Clin Invest,2007.117(12):3633-41.
[74]SUZUKI, R., TAKIZAWA, T, NEGISHI, Y, et al., Effective gene delivery with novel liposomal bubbles and ultrasonic destruction technology. Int J Pharm,2008.354(1-2):49-55.
[75]MORRIS, K.V. and ROSSI, J.J., Lentiviral-mediated delivery of sirnas for antiviral therapy. Gene Ther,2006.13(6):553-8.
[76]ZHAO, Z.Q., Postconditioning in reperfusion injury:A status report Cardiovasc Drugs Ther, 2010.24(3):265-79.
[77]NIIZUMA, K., YOSHIOKA, H., CHEN, H., et al., Mitochondrial and apoptotic neuronal death signaling pathways in cerebral ischemia. Biochim Biophys Acta,2009.1802(1):92-9.
[78]CHAN, P.H., Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab,2001.21(1):2-14.
[79]SENER, G., KABASAKAL, L., CETINEL, S., et al., Leukotriene receptor blocker montelukast protects against burn-induced oxidative injury of the skin and remote organs. Burns,2005. 31(5):587-96.
[80]TUGTEPE, H., SENER, G., CETINEL, S., et al., Oxidative renal damage in pyelonephritic rats is ameliorated by montelukast, a selective leukotriene cysltl receptor antagonist. Eur J Pharmacol,2007.557(1):69-75.
[81]KALONIA, H., KUMAR, P., KUMAR, A., et al., Protective effect of montelukast against quinolinic acid/malonic acid induced neurotoxicity:Possible behavioral, biochemical, mitochondrial and tumor necrosis factor-alpha level alterations in rats. Neuroscience,2010. 171(1):284-99.
[82]MUELLER, C.F., BECHER, M.U., ZIMMER, S., et al., Angiotensin ii triggers release of leukotriene c4 in vascular smooth muscle cells via the multidrug resistance-related protein 1. Mol Cell Biochem,2010.333(1-2):261-7.
[83]MOHAMADIN, A.M., ELBERRY, A.A., ELKABLAWY, M.A., et al., Montelukast, a leukotriene receptor antagonist abrogates lipopolysaccharide-induced toxicity and oxidative stress in rat liver. Pathophysiology,2011.18(3):235-42.
[84]BECHER, U.M., GHANEM, A., TIYERILI, V., et al., Inhibition of leukotriene c4 action reduces oxidative stress and apoptosis in cardiomyocytes and impedes remodeling after myocardial injury. J Mol Cell Cardiol,2011.50(3):570-7.
[85]COSKUN, A.K., YIGITER, M., ORAL, A., et al., The effects of montelukast on antioxidant enzymes and proinflammatory cytokines on the heart, liver, lungs, and kidneys in a rat model of cecal ligation and puncture-induced sepsis. ScientificWorldJournal,2011.11:1341-56.
[86]OFFER, S., SHOSEYOV, D., BIBI, H., et al., A leukotriene receptor antagonist modulates inos in the lung and in a leukotriene-free cell model. Nitric Oxide,2003.9(1):10-7.
[87]SILVA, R.C., LANDGRAF, M.A., HIYANE, M.I., et al., Leukotrienes produced in allergic lung inflammation activate alveolar macrophages. Cell Physiol Biochem,2010.26(3):319-26.
[88]KABASAKAL, L., SENER, G, CETINEL, S., et al., Burn-induced oxidative injury of the gut is ameliorated by the leukotriene receptor blocker montelukast. Prostaglandins Leukot Essent Fatty Acids,2005.72(6):431-40.
[89]DENGIZ, G.O., ODABASOGLU, F., HALICI, Z., et al., Gastroprotective and antioxidant effects of montelukast on indomethacin-induced gastric ulcer in rats. J Pharmacol Sci,2007. 105(1):94-102.
[90]ANDERSON, R., THERON, A.J., GRAVETT, C.M., et al., Montelukast inhibits neutrophil pro-inflammatory activity by a cyclic amp-dependent mechanism. Br J Pharmacol,2009. 156(1):105-15.
[91]MUTHURAMAN, A. and SOOD, S., Antisecretory, antioxidative and antiapoptotic effects of montelukast on pyloric ligation and water immersion stress induced peptic ulcer in rat. Prostaglandins Leukot Essent Fatty Acids,2010.83(1):55-60.
[92]LY, J.D., GRUBB, D.R., and LAWEN, A., The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis,2003.8(2):115-28.
[93]SUSIN, S.A., ZAMZAMI, N., and KROEMER, G, Mitochondria as regulators of apoptosis: Doubt no more. Biochim Biophys Acta,1998.1366(1-2):151-65.
[94]IIJIMA, T., MISHIMA, T., AKAGAWA, K., et al., Mitochondrial hyperpolarization after transient oxygen-glucose deprivation and subsequent apoptosis in cultured rat hippocampal neurons. Brain Res,2003.993(1-2):140-5.
[95]IIJIMA, T., MISHIMA, T., AKAGAWA, K., et al., Neuroprotective effect of propofol on necrosis and apoptosis following oxygen-glucose deprivation--relationship between mitochondrial membrane potential and mode of death. Brain Res,2006.1099(1):25-32.
[96]IIJIMA, T., MISHIMA, T, TOHYAMA, M., et al., Mitochondrial membrane potential and intracellular atp content after transient experimental ischemia in the cultured hippocampal neuron. Neurochem Int,2003.43(3):263-9.
[97]JIANG, Y., BORRELLI, L., BACSKAI, B.J., et al., P2y6 receptors require an intact cysteinyl leukotriene synthetic and signaling system to induce survival and activation of mast cells. J Immunol,2009.182(2):1129-37.
[98]MAMEDOVA, L., CAPRA, V., ACCOMAZZO, M.R., et al., Cysltl leukotriene receptor antagonists inhibit the effects of nucleotides acting at p2y receptors. Biochem Pharmacol,2005. 71(1-2):115-25.
[99]LANGLOIS, A., FERLAND, C., TREMBLAY, G.M., et al., Montelukast regulates eosinophil protease activity through a leukotriene-independent mechanism. J Allergy Clin Immunol,2006. 118(1):113-9.
[100]ROBINSON, A.J., KASHANIN, D., ODOWD, F., et al., Montelukast inhibition of resting and gm-csf-stimulated eosinophil adhesion to vcam-1 under flow conditions appears independent of cyslt(1)r antagonism. J Leukoc Biol,2008.83(6):1522-9.
[101]DI GENNARO, A., CARNINI, C., BUCCELLATI, C., et al., Cysteinyl-leukotrienes receptor activation in brain inflammatory reactions and cerebral edema formation:A role for transcellular biosynthesis of cysteinyl-leukotrienes. FASEB J,2004.18(7):842-4.
[102]BALLERINI, P., DI IORIO, P., CICCARELLI, R., et al., P2yl and cysteinyl leukotriene receptors mediate purine and cysteinyl leukotriene co-release in primary cultures of rat microglia Int J Immunopathol Pharmacol,2005.18(2):255-68.
[103]GIFFARD, R.G and SWANSON, R.A., Ischemia-induced programmed cell death in astrocytes. Glia,2005.50(4):299-306.
[104]ANDERSON, M.F., BLOMSTRAND, F., BLOMSTRAND, C., et al., Astrocytes and stroke: Networking for survival? Neurochem Res,2003.28(2):293-305.
[105]AYATA, C. and ROPPER, A.H., Ischaemic brain oedema. J Clin Neurosci,2002.9(2):113-24.
[106]GURER, G, GURSOY-OZDEMIR, Y., ERDEMLI, E., et al., Astrocytes are more resistant to focal cerebral ischemia than neurons and die by a delayed necrosis. Brain Pathol,2009. 19(4):630-41.
[107]WARD, S.A., RANSOM, P. A., BOOTH, P.L., et al., Characterization of ramified microglia in tissue culture:Pinocytosis and motility. J Neurosci Res,1991.29(1):13-28.
[108]GRAEBER, M.B. and STREIT, W.J., Microglia:Biology and pathology. Acta Neuropathol, 2009.119(1):89-105.
[109]STOLZING, A., WENGNER, A., and GRUNE, T., Degradation of oxidized extracellular proteins by microglia Arch Biochem Biophys,2002.400(2):171-9.
[110]NAPOLI, I. and NEUMANN, H., Microglial clearance function in health and disease. Neuroscience,2009.158(3):1030-8.
[111]CANDELARIO-JALIL, E., DE OLIVEIRA, A.C., GRAF, S., et al., Resveratrol potently reduces prostaglandin e2 production and free radical formation in lipopolysaccharide-activated primary rat microglia J Neuroinflammation,2007.4:25.
[112]NI, M. and ASCHNER, M., Neonatal rat primary microglia:Isolation, culturing, and selected applications. Curr Protoc Toxicol,2010. Chapter 12:Unit 12 17.
[113]HUANG, X.Q., ZHANG, X.Y., WANG, X.R., et al., Transforming growth factor betal-induced astrocyte migration is mediated in part by activating 5-lipoxygenase and cysteinyl leukotriene receptor 1. J Neuroinflammation,2012.9:145.
[114]KLEGERIS, A. and MCGEER, P.L., Toxicity of human monocytic thp-1 cells and microglia toward sh-sy5y neuroblastoma cells is reduced by inhibitors of 5-lipoxygenase and its activating protein flap. J Leukoc Biol,2003.73(3):369-78.
[115]BACK, M., Leukotriene signaling in atherosclerosis and ischemia. Cardiovasc Drugs Ther, 2009.23(1):41-8.
[116]PARHAMIFAR, L., SIME, W., YUDINA, Y., et al., Ligand-induced tyrosine phosphorylation of cysteinyl leukotriene receptor 1 triggers internalization and signaling in intestinal epithelial cells. PLoS One,2010.5(12):e14439.
[117]ICHIYAMA, T., KAJIMOTO, M., HASEGAWA, M., et al., Cysteinyl leukotrienes enhance tumour necrosis factor-alpha-induced matrix metalloproteinase-9 in human monocytes/macrophages. Clin Exp Allergy,2007.37(4):608-14.
[118]XIA, W., HAN, J., HUANG, G, et al., Inflammation in ischaemic brain injury:Current advances and future perspectives. Clin Exp Pharmacol Physiol,2010.37(2):253-8.
[119]WEINSTEIN, J.R., KOERNER, I.P., and MOLLER, T., Microglia in ischemic brain injury. Future Neurol,2010.5(2):227-246.
[120]CEULEMANS, A.G, ZGAVC, T., KOOIJMAN, R., et al., The dual role of the neuroinflammatory response after ischemic stroke:Modulatory effects of hypothermia. J Neuroinflammation,2010.7:74.
[121]THOMPSON, C, CLOUTIER, A., BOSSE, Y., et al., Signaling by the cysteinyl-leukotriene receptor 2. Involvement in chemokine gene transcription. J Biol Chem,2008.283(4):1974-84.
[1]GUO, M.F., YU, J.Z., and MA, C.G, Mechanisms related to neuron injury and death in cerebral hypoxic ischaemia. Folia Neuropathol,2011.49(2):78-87.
[2]LAU, A. and TYMIANSKI, M., Glutamate receptors, neurotoxicity and neurodegeneration. Pflugers Arch,2010.460(2):525-42.
[3]BRADLEY, S.R., MARINO, M.J., WITTMANN, M., et al., Activation of group ii metabotropic glutamate receptors inhibits synaptic excitation of the substantia nigra pars reticulata. J Neurosci,2000.20(9):3085-94.
[4]BREYSSE, N., BAUNEZ, C., SPOOREN, W., et al., Chronic but not acute treatment with a metabotropic glutamate 5 receptor antagonist reverses the akinetic deficits in a rat model of parkinsonism. J Neurosci,2002.22(13):5669-78.
[5]KIRSCHSTEIN, T., BAUER, M., MULLER, L., et al., Loss of metabotropic glutamate receptor-dependent long-term depression via downregulation of mglur5 after status epilepticus. J Neurosci,2007.27(29):7696-704.
[6]KAWAHARA, Y. and KWAK, S., Excitotoxicity and als:What is unique about the ampa receptors expressed on spinal motor neurons? Amyotroph Lateral Scler Other Motor Neuron Disord,2005.6(3):131-44.
[7]BROUNS, R. and DE DEYN, P.P., The complexity of neurobiological processes in acute ischemic stroke. Clin Neurol Neurosurg,2009. 111(6):483-95.
[8]BOBIK, M., ELLISMAN, M.H., RUDY, B., et al., Potassium channel subunit kv3.2 and the water channel aquaporin-4 are selectively localized to cerebellar pinceau. Brain Res,2004. 1026(2):168-78.
[9]KOFUJI, P. and NEWMAN, E.A., Potassium buffering in the central nervous system. Neuroscience,2004.129(4):1045-56.
[10]LIANG, D., DAWSON, T.M., and DAWSON, V.L., What have genetically engineered mice taught us about ischemic injury? Curr Mol Med,2004.4(2):207-25.
[11]LOVE, S., Apoptosis and brain ischaemia. Prog Neuropsychopharmacol Biol Psychiatry,2003. 27(2):267-82.
[12]HARE, W.A. and WHEELER, L., Experimental glutamatergic excitotoxicity in rabbit retinal ganglion cells:Block by memantine. Invest Ophthalmol Vis Sci,2009.50(6):2940-8.
[13]SATTLER, R., XIONG, Z., LU, W.Y., et al., Specific coupling of nmda receptor activation to nitric oxide neurotoxicity by psd-95 protein. Science,1999.284(5421):1845-8.
[14]MEHTA, S.L., MANHAS, N., and RAGHUBIR, R., Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev,2007.54(1):34-66.
[15]CHANG, P.K., VERBICH, D., and MCKINNEY, R.A., Ampa receptors as drug targets in neurological disease-advantages, caveats, and future outlook. Eur J Neurosci,2012. 35(12):1908-16.
[16]PALMER, C.L., COTTON, L., and HENLEY, J.M., The molecular pharmacology and cell biology of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors. Pharmacol Rev,2005.57(2):253-77.
[17]KWAK, S. and KAWAHARA, Y., Deficient rna editing of glur2 and neuronal death in amyotropic lateral sclerosis. J Mol Med (Berl),2005.83(2):110-20.
[18]PELLEGRINI-GIAMPIETRO, D.E., GORTER, J.A., BENNETT, M.V., et al., The glur2 (glur-b) hypothesis:Ca(2+)-permeable ampa receptors in neurological disorders. Trends Neurosci,1997.20(10):464-70.
[19]KWAK, S., HIDEYAMA, T, YAMASHITA, T., et al., Ampa receptor-mediated neuronal death in sporadic als. Neuropathology,2010.30(2):182-8.
[20]SOMMER, C. and KIESSLING, M., Ischemia and ischemic tolerance induction differentially regulate protein expression of glurl, glur2, and ampa receptor binding protein in the gerbil hippocampus:Glur2 (glur-b) reduction does not predict neuronal death. Stroke,2002. 33(4):1093-100.
[21]FRIEDMAN, L.K., AVALLONE, J.M., and MAGRYS, B., Maturational effects of single and multiple early-life seizures on ampa receptors in prepubescent hippocampus. Dev Neurosci, 2007.29(6):427-37.
[22]AARTS, M.M. and TYMIANSKI, M., Molecular mechanisms underlying specificity of excitotoxic signaling in neurons. Curr Mol Med,2004.4(2):137-47.
[23]AKINS, P.T. and ATKINSON, R.P., Glutamate ampa receptor antagonist treatment for ischaemic stroke. Curr Med Res Opin,2002.18 Suppl 2:s9-13.
[24]CRACK, P.J. and TAYLOR, J.M., Reactive oxygen species and the modulation of stroke. Free Radic Biol Med,2005.38(11):1433-44.
[25]KIMURA, H., GULES, I., MEGURO, T, et al., Cytotoxicity of cytokines in cerebral microvascular endothelial cell. Brain Res,2003.990(1-2):148-56.
[26]DIRNAGL, U., IADECOLA, C., and MOSKOWITZ, M.A., Pathobiology of ischaemic stroke: An integrated view. Trends Neurosci,1999.22(9):391-7.
[27]FRASER, P. A., The role of free radical generation in increasing cerebrovascular permeability. Free Radic Biol Med,2011.51(5):967-77.
[28]ALFADDA, A.A. and SALLAM, R.M., Reactive oxygen species in health and disease. J Biomed Biotechnol,2012.2012:936486.
[29]BRIEGER, K., SCHIAVONE, S., MILLER, F.J., JR., et al., Reactive oxygen species:From health to disease. Swiss Med Wkly,2012.142:w13659.
[30]NIIZUMA, K., YOSHIOKA, H., CHEN, H., et al., Mitochondrial and apoptotic neuronal death signaling pathways in cerebral ischemia. Biochim Biophys Acta,2009.1802(1):92-9.
[31]CHAN, P.H., Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab,2001.21(1):2-14.
[32]ZHAO, Z.Q., Postconditioning in reperfusion injury:A status report. Cardiovasc Drugs Ther, 2010.24(3):265-79.
[33]SAEED, S.A., SHAD, K.F., SALEEM, T., et al., Some new prospects in the understanding of the molecular basis of the pathogenesis of stroke. Exp Brain Res,2007.182(1):1-10.
[34]JUNG, J.E., KIM, G.S., CHEN, H., et al., Reperfusion and neurovascular dysfunction in stroke: From basic mechanisms to potential strategies for neuroprotection Mol Neurobiol,2010. 41(2-3):172-9.
[35]NAKKA, V.P., GUSAIN, A., MEHTA, S.L., et al., Molecular mechanisms of apoptosis in cerebral ischemia:Multiple neuroprotective opportunities. Mol Neurobiol,2008.37(1):7-38.
[36]KIEWERT, C., HARTMANN, J., STOLL, J., et al., Ngp1-01 is a brain-permeable dual blocker of neuronal voltage-and ligand-operated calcium channels. Neurochem Res,2006. 31(3):395-9.
[37]MATSUDA, T, ARAKAWA, N., TAKUMA, K., et al., Sea0400, a novel and selective inhibitor of the na+-ca2+exchanger, attenuates reperfusion injury in the in vitro and in vivo cerebral ischemic models. J Pharmacol Exp Ther,2001.298(1):249-56.
[38]RACAY, P., TATARKOVA, Z., CHOMOVA, M., et at,, Mitochondrial calcium transport and mitochondrial dysfunction after global brain ischemia in rat hippocampus. Neurochem Res, 2009.34(8):1469-78.
[39]BROOKES, P.S., YOON, Y., ROBOTHAM, J.L., et al., Calcium, atp, and ros:A mitochondrial love-hate triangle. Am J Physiol Cell Physiol,2004.287(4):C817-33.
[40]ICHAS, F. and MAZAT, J.P., From calcium signaling to cell death:Two conformations for the mitochondrial permeability transition pore. Switching from low-to high-conductance state. Biochim Biophys Acta,1998.1366(1-2):33-50.
[41]ROSENBERG, G.A., ESTRADA, E.Y., and DENCOFF, J.E., Matrix metalloproteinases and timps are associated with blood-brain barrier opening after reperfusion in rat brain. Stroke, 1998,29(10):2189-95.
[42]GROENENDYK, J., LYNCH, J., and MICHALAK, M., Calreticulin, ca2+, and calcineurin-signaling from the endoplasmic reticulum. Mol Cells,2004.17(3):383-9.
[43]ZHANG, W., PETROVIC, J.M., CALLAGHAN, D., et al, Evidence that hypoxia-inducible factor-1 (hif-1) mediates transcriptional activation of interleukin-lbeta (il-1beta) in astrocyte cultures. J Neuroimmunol, 2006.174(1-2):63-73.
[44]FREDERICKSON, C.J., GIBLIN, L.J., KREZEL, A., et al., Concentrations of extracellular free zinc (pzn)e in the central nervous system during simple anesthetization, ischemia and reperfusion Exp Neurol,2006.198(2):285-93.
[45]KITAMURA, Y., IIDA, Y., ABE, J., et al., Release of vesicular zn2+in a rat transient middle cerebral artery occlusion model Brain Res Bull,2006.69(6):622-5.
[46]SENSI, S.L., PAOLETTI, P., BUSH, A.I., et at, Zinc in the physiology and pathology of the ens. Nat Rev Neurosci,2009.10(11):780-91.
[47]MARET, W., Metallothionein redox biology in the cytoprotective and cytotoxic functions of zinc. Exp Gerontol,2008.43(5):363-9.
[48]AIZENMAN, E., STOUT, A.K., HARTNETT, K.A., et al., Induction of neuronal apoptosis by thiol oxidation:Putative role of intracellular zinc release. J Neurochem,2000.75(5):1878-88.
[49]SENSI, S.L., TON-THAT, D., SULLIVAN, P.G, et al., Modulation of mitochondrial function by endogenous zn2+ pools. Proc Natl Acad Sci U S A,2003.100(10):6157-62.
[50]GAZARYAN, I.G., KRASINSKAYA, I.P., KRISTAL, B.S., et al., Zinc irreversibly damages major enzymes of energy production and antioxidant defense prior to mitochondrial permeability transition. J Biol Chem,2007.282(33):24373-80.
[51]WEISS, J.H., SENSI, S.L., and KOH, J.Y., Zn(2+):A novel ionic mediator of neural injury in brain disease. Trends Pharmacol Sci,2000.21(10):395-401.
[52]DINELEY, K.E., RICHARDS, L.L., VOTYAKOVA, T.V., et al., Zinc causes loss of membrane potential and elevates reactive oxygen species in rat brain mitochondria. Mitochondrion,2005. 5(1):55-65.
[53]JIANG, D., SULLIVAN, P.G, SENSI, S.L., et al., Zn(2+) induces permeability transition pore opening and release of pro-apoptotic peptides from neuronal mitochondria J Biol Chem,2001. 276(50):47524-9.
[54]KOH, J.Y., SUH, S.W., GWAG, B.J., et al., The role of zinc in selective neuronal death after transient global cerebral ischemia. Science,1996.272(5264):1013-6.
[55]SUH, S.W., CHEN, J.W., MOTAMEDI, M., et al., Evidence that synaptically-released zinc contributes to neuronal injury after traumatic brain injury. Brain Res,2000.852(2):268-73.
[56]MEDVEDEVA, Y.V., LIN, B., SHUTTLEWORTH, C.W., et al., Intracellular zn2+ accumulation contributes to synaptic failure, mitochondrial depolarization, and cell death in an acute slice oxygen-glucose deprivation model of ischemia J Neurosci,2009.29(4):1105-14.
[57]HONG, S.J., DAWSON, T.M., and DAWSON, V.L., Nuclear and mitochondrial conversations in cell death:Parp-1 and aif signaling. Trends Pharmacol Sci,2004.25(5):259-64.
[58]SUSIN, S.A., ZAMZAMI, N., and KROEMER, G, Mitochondria as regulators of apoptosis: Doubt no more. Biochim Biophys Acta,1998.1366(1-2):151-65.
[59]LY, J.D., GRUBB, D.R., and LAWEN, A., The mitochondrial membrane potential (deltapsi(m)) in apoptosis; an update. Apoptosis,2003.8(2):115-28.
[60]BOUJRAD, H., GUBKINA, O., ROBERT, N., et al., Aif-mediated programmed necrosis:A highly regulated way to die. Cell Cycle,2007.6(21):2612-9.
[61]SOLAROGLU, I., TSUBOKAWA, T., CAHILL, J., et al., Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat Neuroscience, 2006.143(4):965-74.
[62]NAKAGAWA, T., ZHU, H., MORISHIMA, N., et al., Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta Nature,2000. 403(6765):98-103.
[63]RAO, R.V., HERMEL, E., CASTRO-OBREGON, S., et al., Coupling endoplasmic reticulum stress to the cell death program. Mechanism of caspase activation. J Biol Chem,2001. 276(36):33869-74.
[64]LIU, T, CLARK, R.K., MCDONNELL, P.C., et al., Tumor necrosis factor-alpha expression in ischemic neurons. Stroke,1994.25(7):1481-8.
[65]BUTTINI, M., APPEL, K., SAUTER, A., et al., Expression of tumor necrosis factor alpha after focal cerebral ischaemia in the rat Neuroscience,1996.71(1):1-16.
[66]WANG, X., YUE, T.L., BARONE, F.C., et al., Concomitant cortical expression of tnf-alpha and il-1 beta mrnas follows early response gene expression in transient focal ischemia. Mol Chem Neuropathol,1994.23(2-3):103-14.
[67]TOMIMOTO, H., AKIGUCHI, I., WAKITA, H., et al., Glial expression of cytokines in the brains of cerebrovascular disease patients. Acta Neuropathol,1996.92(3):281-7.
[68]SAIRANEN, T., CARPEN, O., KARJALAINEN-LINDSBERG, M.L., et al., Evolution of cerebral tumor necrosis factor-alpha production during human ischemic stroke. Stroke,2001. 32(8):1750-8.
[69]VILA, N., CASTILLO, J., DAVALOS, A., et al., Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke,2000.31(10):2325-9.
[70]ZAREMBA, J., SKROBANSKI, P., and LOSY, J., Tumour necrosis factor-alpha is increased in the cerebrospinal fluid and serum of ischaemic stroke patients and correlates with the volume of evolving brain infarct. Biomed Pharmacother,2001.55(5):258-63.
[71]CASTELLANOS, M., CASTILLO, J., GARCIA, M.M., et al., Inflammation-mediated damage in progressing lacunar infarctions:A potential therapeutic target Stroke,2002.33(4):982-7.
[72]YANG, G.Y., GONG, C., QIN, Z., et al., Inhibition of tnfalpha attenuates infarct volume and icam-1 expression in ischemic mouse brain. Neuroreport,1998.9(9):2131-4.
[73]LAVINE, S.D., HOFMAN, F.M., and ZLOKOVIC, B.V., Circulating antibody against tumor necrosis factor-alpha protects rat brain from reperfusion injury. J Cereb Blood Flow Metab, 1998.18(1):52-8.
[74]WANG, C.X. and SHUAIB, A., Involvement of inflammatory cytokines in central nervous system injury. Prog Neurobiol,2002.67(2):161-72.
[75]BARONE, F.C., ARVIN, B., WHITE, R.F., et al., Tumor necrosis factor-alpha. A mediator of focal ischemic brain injury. Stroke,1997.28(6):1233-44.
[76]BRUCE, A.J., BOLING, W., KINDY, M.S., et al., Altered neuronal and microglial responses to excitotoxic and ischemic brain injury in mice lacking tnf receptors. Nat Med,1996. 2(7):788-94.
[77]ZOU, J.Y. and CREWS, F.T., Tnf alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures:Neuroprotection by nf kappa b inhibition. Brain Res,2005.1034(1-2):11-24.
[78]GINIS, I., JAISWAL, R., KLIMANIS, D., et al., Tnf-alpha-induced tolerance to ischemic injury involves differential control of nf-kappab transactivation:The role of nf-kappab association with p300 adaptor. J Cereb Blood Flow Metab,2002.22(2):142-52.
[79]PRADILLO, J.M., ROMERA, C., HURTADO, O., et al., Tnfrl upregulation mediates tolerance after brain ischemic preconditioning. J Cereb Blood Flow Metab,2005.25(2):193-203.
[80]PRADILLO, J.M., HURTADO, O., ROMERA, C., et al., Tnfrl mediates increased neuronal membrane eaat3 expression after in vivo cerebral ischemic preconditioning. Neuroscience, 2006.138(4):1171-8.
[81]DINARELLO, C.A., Interleukin-1 and interleukin-1 antagonism. Blood,1991.77(8):1627-52.
[82]DRIPPS, D.J., BRANDHUBER, B.J., THOMPSON, R.C., et al., Interleukin-1 (il-1) receptor antagonist binds to the 80-kda il-1 receptor but does not initiate il-1 signal transduction. J Biol Chem,1991.266(16):10331-6.
[83]KOGA, S., OGAWA, S., KUWABARA, K., et al., Synthesis and release of interleukin 1 by reoxygenated human mononuclear phagocytes. J Clin Invest,1992.90(3):1007-15.
[84]ROTHWELL, N.J., Functions and mechanisms of interleukin 1 in the brain. Trends Pharmacol Sci,1991.12(11):430-6.
[85]MINAMI, M., KURAISHI, Y., and SATOH, M., Effects of kainic acid on messenger rna levels of il-1 beta, il-6, tnf alpha and lif in the rat brain. Biochem Biophys Res Commun,1991. 176(2):593-8.
[86]BUTTINI, M. and BODDEKE, H., Peripheral lipopolysaccharide stimulation induces interleukin-1 beta messenger rna in rat brain microglial cells. Neuroscience,1995. 65(2):523-30.
[87]BUTTINI, M., SAUTER, A., and BODDEKE, H.W., Induction of interleukin-1 beta mrna after focal cerebral ischaemia in the rat. Brain Res Mol Brain Res,1994.23(1-2):126-34.
[88]HAQQANI, A.S., NESIC, M., PRESTON, E., et al., Characterization of vascular protein expression patterns in cerebral ischemia/reperfusion using laser capture microdissection and icat-nanolc-ms/ms. FASEB J,2005.19(13):1809-21.
[89]DAVIES, C.A., LODDICK, S.A., TOULMOND, S., et al., The progression and topographic distribution of interleukin-1 beta expression after permanent middle cerebral artery occlusion in the rat. J Cereb Blood Flow Metab,1999.19(1):87-98.
[90]YAMASAKI, Y., MATSUURA, N., SHOZUHARA, H., et al., Interleukin-1 as a pathogenetic mediator of ischemic brain damage in rats. Stroke,1995.26(4):676-80; discussion 681.
[91]RELTON, J.K., MARTIN, D., THOMPSON, R.C., et al., Peripheral administration of interleukin-1 receptor antagonist inhibits brain damage after focal cerebral ischemia in the rat. Exp Neurol,1996.138(2):206-13.
[92]YANG, G.Y., ZHAO, Y.J., DAVIDSON, B.L., et al., Overexpression of interleukin-1 receptor antagonist in the mouse brain reduces ischemic brain injury. Brain Res,1997.751(2):181-8.
[93]PINTEAUX, E., ROTHWELL, N. J., and BOUTIN, H., Neuroprotective actions of endogenous interleukin-1 receptor antagonist (il-lra) are mediated by glia Glia,2006.53(5):551-6.
[94]CARLSON, N.G, WIEGGEL, W.A., CHEN, J., et al., Inflammatory cytokines il-1 alpha, il-1 beta, il-6, and tnf-alpha impart neuroprotection to an excitotoxin through distinct pathways. J Immunol,1999.163(7):3963-8.
[95]STRIJBOS, P.J. and ROTHWELL, N.J., Interleukin-1 beta attenuates excitatory amino acid-induced neurodegeneration in vitro:Involvement of nerve growth factor. J Neurosci,1995. 15(5Pt 1):3468-74.
[96]CASTILLO, J. and RODRIGUEZ, I., Biochemical changes and inflammatory response as markers for brain ischaemia:Molecular markers of diagnostic utility and prognosis in human clinical practice. Cerebrovasc Dis,2004.17 Suppl 1:7-18.
[97]SMITH, C.J., EMSLEY, H.C., GAVIN, C.M., et al., Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome. BMC Neurol,2004.4:2.
[98]TARKOWSKI, E., ROSENGREN, L., BLOMSTRAND, C., et al., Intrathecal release of pro-and anti-inflammatory cytokines during stroke. Clin Exp Immunol,1997.110(3):492-9.
[99]SPERA, P.A., ELLISON, J.A., FEUERSTEIN, G.Z., et al.,11-10 reduces rat brain injury following focal stroke. Neurosci Lett,1998.251(3):189-92.
[100]OOBOSHI, H., IBAYASHI, S., SHICHITA, T., et al., Postischemic gene transfer of interleukin-10 protects against both focal and global brain ischemia. Circulation,2005. 111(7):913-9.
[101]VAN EXEL, E., GUSSEKLOO, J., DE CRAEN, A.J., et al., Inflammation and stroke:The leiden 85-plus study. Stroke,2002.33(4):1135-8.
[102]VILA, N., CASTILLO, J., DAVALOS, A., et al., Levels of anti-inflammatory cytokines and neurological worsening in acute ischemic stroke. Stroke,2003.34(3):671-5.
[103]KLEMPT, N.D., SIRIMANNE, E., GUNN, A.J., et al., Hypoxia-ischemia induces transforming growth factor beta 1 mrna in the infant rat brain. Brain Res Mol Brain Res,1992. 13(1-2):93-101.
[104]WIESSNER, C., GEHRMANN, J., LINDHOLM, D., et al., Expression of transforming growth factor-beta 1 and interleukin-1 beta mrna in rat brain following transient forebrain ischemia Acta Neuropathol,1993.86(5):439-46.
[105]PAL, G., VINCZE, C., RENNER, E., et al., Time course, distribution and cell types of induction of transforming growth factor betas following middle cerebral artery occlusion in the rat brain. PLoS One,2012.7(10):e46731.
[106]JOHNSTON, R.E., DILLON-CARTER, O., FREED, W.J., et al., Trophic factor secreting kidney cell lines:In vitro characterization and functional effects following transplantation in ischemic rats. Brain Res,2001.900(2):268-76.
[107]BENVENISTE, E.N., Cytokine actions in the central nervous system. Cytokine Growth Factor Rev,1998.9(3-4):259-75.
[108]GROSS, C.E., BEDNAR, M.M., HOWARD, D.B., et al., Transforming growth factor-beta 1 reduces infarct size after experimental cerebral ischemia in a rabbit model. Stroke,1993. 24(4):558-62.
[109]PANG, L., YE, W., CHE, X.M., et al., Reduction of inflammatory response in the mouse brain with adenoviral-mediated transforming growth factor-ssl expression. Stroke,2001. 32(2):544-52.
[110]MORI, E., DEL ZOPPO, G.J., CHAMBERS, J.D., et al., Inhibition of polymorphonuclear leukocyte adherence suppresses no-reflow after focal cerebral ischemia in baboons. Stroke, 1992.23(5):712-8.
[111]YU, G.L., WEI, E.Q., ZHANG, S.H., et al., Montelukast, a cysteinyl leukotriene receptor-1 antagonist, dose-and time-dependently protects against focal cerebral ischemia in mice. Pharmacology,2005.73(1):31-40.
[112]NIJBOER, C.H., HEIJNEN, C.J., GROENENDAAL, F., et al., A dual role of the nf-kappab pathway in neonatal hypoxic-ischemic brain damage. Stroke,2008.39(9):2578-86.
[113]COJOCARU, I.M., MUSUROI, C., IACOB, S., et al, Investigation of tnf-alpha, il-6, il-8 and of procalcitonin in patients with neurologic complications in sepsis. Rom J Intern Med.2003. 41(1):83-93.
[114]STEPHENSON, D., YIN, T., SMALSTIG, E.B., et al., Transcription factor nuclear factor-kappa b is activated in neurons after focal cerebral ischemia. J Cereb Blood Flow Metab,2000. 20(3):592-603.
[115]FABIAN, R.H., PEREZ-POLO, J.R., and KENT, T.A., A decoy oligonucleotide inhibiting nuclear factor-kappab binding to the iggkappab consensus site reduces cerebral injury and apoptosis in neonatal hypoxic-ischemic encephalopathy. J Neurosci Res,2007.85(7):1420-6.
[116]SCHWAB, J.M., NGUYEN, T.D., POSTLER, E., et al., Selective accumulation of cyclooxygenase-1-expressing microglial cells/macrophages in lesions of human focal cerebral ischemia Acta Neuropathol,2000.99(6):609-14.
[117]IADECOLA, C, SUGIMOTO, K., NIWA, K., et al., Increased susceptibility to ischemic brain injury in cyclooxygenase-1-deficient mice. J Cereb Blood Flow Metab,2001.21(12):1436-41.
[118]CANDELARIO-JALIL, E., GONZALEZ-FALCON, A., GARCIA-CABRERA, M., et al., Assessment of the relative contribution of cox-1 and cox-2 isoforms to ischemia-induced oxidative damage and neurodegeneration following transient global cerebral ischemia. J Neurochem,2003.86(3):545-55.
[119]NOGAWA, S., ZHANG, F., ROSS, M.E., et al., Cyclo-oxygenase-2 gene expression in neurons contributes to ischemic brain damage. J Neurosci,1997.17(8):2746-55.
[120]KINOUCHI, H., HUANG, H., ARAI, S., et al., Induction of cyclooxygenase-2 messenger rna after transient and permanent middle cerebral artery occlusion in rats:Comparison with c-fos messenger rna by using in situ hybridization. J Neurosurg,1999.91(6):1005-12.
[121]PLANAS, A.M., SORIANO, M.A., RODRIGUEZ-FARRE, E., et al., Induction of cyclooxygenase-2 mrna and protein following transient focal ischemia in the rat brain. Neurosci Lett,1995.200(3):187-90.
[122]SAIRANEN, T., RISTIMAKI, A., KARJALAINEN-LINDSBERG, M.L.. et al., Cyclooxygenase-2 is induced globally in infarcted human brain. Ann Neurol,1998. 43(6):738-47.
[123]SUGIMOTO, K. and IADECOLA, C., Delayed effect of administration of cox-2 inhibitor in mice with acute cerebral ischemia Brain Res,2003.960(1-2):273-6.
[124]DORE, S., OTSUKA, T., MITO, T., et al., Neuronal overexpression of cyclooxygenase-2 increases cerebral infarction. Ann Neurol,2003.54(2):155-62.
[125]FUNK, C.D., Prostaglandins and leukotrienes:Advances in eicosanoid biology. Science,2001. 294(5548):1871-5.
[126]MONTUSCHI, P. and PETERS-GOLDEN, M.L., Leukotriene modifiers for asthma treatment. Clin Exp Allergy,2010.40(12):1732-41.
[127]PETERS-GOLDEN, M., GLEASON, M.M., and TOGIAS, A., Cysteinyl leukotrienes: Multi-functional mediators in allergic rhinitis. Clin Exp Allergy,2006.36(6):689-703.
[128]BLACK, K.L., HOFF, J.T., MCGILLICUDDY, J.E., et al., Increased leukotriene c4 and vasogenic edema surrounding brain tumors in humans. Ann Neurol,1986.19(6):592-5.
[129]FREIBERG, J.J., DAHL, M., TYBJAERG-HANSEN, A., et al., Leukotriene c4 synthase and ischemic cardiovascular disease and obstructive pulmonary disease in 13,000 individuals. J Mol Cell Cardiol,2009.46(4):579-86.
[130]CICERI, P., RABUFFETTI, M., MONOPOLI, A., et al., Production of leukotrienes in a model of focal cerebral ischaemia in the rat Br J Pharmacol,2001.133(8):1323-9.
[131]DHILLON, H.S., DOSE, J.M., and PRASAD, M.R., Regional generation of leukotriene c4 after experimental brain injury in anesthetized rats. J Neurotrauma,1996.13(12):781-9.
[132]SINGH, R.K., GUPTA, S., DASTIDAR, S., et al., Cysteinyl leukotrienes and their receptors: Molecular and functional characteristics. Pharmacology,2010.85(6):336-49.
[133]KANAOKA, Y. and BOYCE, J.A., Cysteinyl leukotrienes and their receptors:Cellular distribution and function in immune and inflammatory responses. J Immunol,2004. 173(3):1503-10.
[134]KILFEATHER, S.,5-lipoxygenase inhibitors for the treatment of copd. Chest,2002.121(5 Suppl):197S-200S.
[135]MEHRABIAN, M., ALLAYEE, H., WONG, J., et al., Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ Res,2002.91(2):120-6.
[136]STANKE-LABESQUE, F., HARDY, G, VERGNAUD, S., et al., Involvement of cysteinyl leukotrienes in angiotensin ii-induced contraction in isolated aortas from transgenic (mren-2)27 rats. J Hypertens,2002.20(2):263-72.
[137]WELT, K., FITZL, G, and MARK, B., Lipoxygenase inhibitor flm 5011, an effective protectant of myocardial microvessels against ischemia-reperfusion injury? An ultrastructural-morphometric study. Exp Toxicol Pathol,2000.52(1):27-36.
[138]HENNIG, R., DING, X.Z., TONG, W.G., et al.,5-lipoxygenase and leukotriene b(4) receptor are expressed in human pancreatic cancers but not in pancreatic ducts in normal tissue. Am J Pathol, 2002.161(2):421-8.
[139]SEUFFERLEIN, T., SECKL, M.J., SCHWARZ, E., et al., Mechanisms of nordihydroguaiaretic acid-induced growth inhibition and apoptosis in human cancer cells. Br J Cancer,2002. 86(7):1188-96.
[140]DAGLAR, GO., KAMA, N.A., ATLI, M., et al., Effect of 5-lipoxygenase inhibition on kupffer cell clearance capacity in obstructive jaundiced rats. J Surg Res,2001.96(2):158-62.
[141]MACCARRONE, M., TACCONE-GALLUCCI, M., MELONI, C, et al., Activation of 5-lipoxygenase and related cell membrane lipoperoxidation in hemodialysis patients. J Am Soc Nephrol,1999.10(9):1991-6.
[142]GOULET, J.L., GRIFFITHS, R.C., RUIZ, P., et al., Deficiency of 5-lipoxygenase accelerates renal allograft rejection in mice. J Immunol,2001.167(11):6631-6.
[143]BUTTERLY, D.W., SPURNEY, R.F., RUIZ, P., et al., A role for leukotrienes in cyclosporine nephrotoxicity. Kidney Int,2000.57(6):2586-93.
[144]TOMIMOTO, H., SHIBATA, M., IHARA, M., et al., A comparative study on the expression of cyclooxygenase and 5-lipoxygenase during cerebral ischemia in humans. Acta Neuropathol, 2002.104(6):601-7.
[145]CHU, L.S., WEI, E.Q., YU, GL., et al., Pranlukast reduces neutrophil but not macrophage/microglial accumulation in brain after focal cerebral ischemia in mice. Acta Pharmacol Sin,2006.27(3):282-8.
[146]ZHAO, C.Z., ZHAO, B., ZHANG, X.Y., et al., Cysteinyl leukotriene receptor 2 is spatiotemporally involved in neuron injury, astrocytosis and microgliosis after focal cerebral ischemia in rats. Neuroscience,2011.189:1-11.
[147]SHI, Q.J., XIAO, L., ZHAO, B., et al., Intracerebroventricular injection of hami 3379, a selective cysteinyl leukotriene receptor 2 antagonist, protects against acute brain injury after focal cerebral ischemia in rats. Brain Res,2012.1484:57-67.
[148]WINKING, M., DEINSBERGER, W., JOEDICKE, A., et al., Cysteinyl-leukotriene levels in intracerebral hemorrhage:An edema-promoting factor? Cerebrovasc Dis,1998.8(6):318-26.
[149]QI, L.L., FANG, S.H., SHI, W.Z., et al., Cyslt2 receptor-mediated aqp4 up-regulation is involved in ischemic-like injury through activation of erk and p38 mapk in rat astrocytes. Life Sci,2010.88(1-2):50-6.
[150]WANG, M.L., HUANG, X.J., FANG, S.H., et al., Leukotriene d4 induces brain edema and enhances cyslt2 receptor-mediated aquaporin 4 expression. Biochem Biophys Res Commun, 2006.350(2):399-404.
[151]OHTSUKI, T., MATSUMOTO, M., HAYASHI, Y., et al., Reperfusion induces 5-lipoxygenase translocation and leukotriene c4 production in ischemic brain. Am J Physiol,1995.268(3 Pt 2):H1249-57.
[152]RAO, A.M., HATCHER, J.F., KINDY, M.S., et al., Arachidonic acid and leukotriene c4:Role in transient cerebral ischemia of gerbils. Neurochem Res,1999.24(10):1225-32.
[153]BARBOSA, M.D., ARTHUR, A.S., LOUIS, R.H., et al., The novel 5-lipoxygenase inhibitor abt-761 attenuates cerebral vasospasm in a rabbit model of subarachnoid hemorrhage. Neurosurgery,2001.49(5):1205-12; discussion 1212-3.
[154]SHISHIDO, Y, FURUSHIRO, M., HASHIMOTO, S., et al., Effect of nordihydroguaiaretic acid on behavioral impairment and neuronal cell death after forebrain ischemia Pharmacol Biochem Behav,2001.69(3-4):469-74.
[155]ZHAO, R., SHI, W.Z., ZHANG, Y.M., et al., Montelukast, a cysteinyl leukotriene receptor-1 antagonist, attenuates chronic brain injury after focal cerebral ischaemia in mice and rats. J Pharm Pharmacol,2011.63(4):550-7.
[156]ZHANG, W.P., WEI, E.Q., MEI, R.H., et al., Neuroprotective effect of ono-1078, a leukotriene receptor antagonist, on focal cerebral ischemia in rats. Acta Pharmacol Sin,2002.23(10):871-7.
[157]YU, G.L., WEI, E.Q., WANG, M.L., et al., Pranlukast, a cysteinyl leukotriene receptor-1 antagonist, protects against chronic ischemic brain injury and inhibits the glial scar formation in mice. Brain Res,2005.1053(1-2):116-25.