电针和奥卡西平干预对实验性癫癎大鼠海马炎症损伤的影响及相关研究
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摘要
癫癎是神经系统一种常见的疾病,其在人群中的患病率为0.5%-2%。目前,虽然对于癫癎的研究取得了一定进展,但是对于癫癎的成因及发病机制目前仍不是完全清楚。大量的资料显示,癫癎与中枢神经系统(CNS)的炎症反应关系密切,炎症反应在一定程度上决定了癫癎的发生、发展。有效的阻断脑内炎症反应,可改变神经元的兴奋性,达到抗癫癎的目的。而在CNS炎症反应中,小胶质细胞(Microglia,MG)的激活起着重要作用,激活的MG分泌大量的炎性因子。而在MG表达的诸多炎性细胞因子中,CD40的表达是炎症反应的一个关键。CD40分子是属于TNF受体超家族成员,它通过和其受体CD40L的相互作用,导致激活的MG分泌炎性因子及炎性介质,介导炎症反应。但是CD40介导的炎症反应是否也存在于癫癎后炎症病理损伤中?目前,暂无这方面的相关研究。
针刺疗法是祖国医学中重要的非药物疗法,其在国内外已产生重大影响。研究显示,针刺可通过不同的机制影响炎症反应,调控炎性因子及炎症介质的释放。同时,本课题组在前期的研究显示,在锂-匹罗卡品癫癎模型中,通过电针刺激“大椎”和“百会”二穴位可有效地抑制自发性再发作(SRS)。但是,电针的这一作用,是否和针刺调节癫癎发作后的炎症反应有关?这需要进一步探讨。另外,资料显示,抗癫癎药(AEDs)-卡马西平(Carbamazepine,CBZ)具有抑制炎症反应和神经保护的作用。其不但能够抑制癫癎发作,而且可通过不同机制影响炎症反应过程,缓解炎症反应引起的临床症状。但是,奥卡西平(Oxcarbazepine,OXC)作为CBZ的衍生物,是否也同样具有抗炎作用?是否可通过减轻癫癎发作后的炎症反应而起到脑保护作用?目前,国内外还没有此方面的相关研究。
针对上述问题,本课题选用锂-匹罗卡品癫癎模型,通过免疫组化、Western blot、ELISA等实验方法。首先观察了实验性癫癎大鼠在癫癎持续状态(status epilepticus,SE)后MG,CD40的表达及变化。随后我们通过对癫癎大鼠给予电针刺激“大椎”和“百会”二穴位和OXC的干预,来观察电针或OXC对SE后CD40介导的炎症反应的影响,并且对二者进行对比研究。其次,我们通过Nissl染色等方法观察了电针或OXC干预对SE后大鼠海马神经元损伤的影响。最后,我们进一步观察了电针或OXC干预对SE、SRS的影响。
主要研究结果如下:
(1)SE后大鼠海马不同区域MG增殖、激活,CD40表达增加,并且在激活的MG上CD40表达明显增加,而CD40在星型胶质细胞上未表达。
(2)电针或OXC干预不同程度抑制了SE后大鼠海马MG的增殖、激活及CD40的表达,以OXC最为明显。
(3)电针或OXC干预抑制了SE后大鼠海马TNF-α的表达,并且OXC的抑制作用强于电针刺激。
(4)电针或OXC干预改善了SE后海马神经元的缺失,以CA1区最为显著,OXC的保护作用强于电针刺激。
(5)电针或OXC干预对SE的发生、发展没有影响,但是二者不同程度延长了SRS的潜伏期、减少SRS的发作频率。
综上所述,本课题首次研究了CD40在实验性癫癎大鼠海马的表达,提示CD40介导的炎症反应存在于癫癎的炎症病理损伤机制中;同时,对癫癎大鼠进行电针或OXC干预可不同程度的抑制CD40介导的炎症反应,随后的实验也证实二者具有脑保护和抑制SRS的作用,提示电针或OXC可通过抑制CD40介导的炎症反应而改善海马神经元的损伤,最终影响SRS的发生、发展。因此,本研究不仅为电针治疗癫癎提供了理论基础和实验资料,而且为研究AEDs在“癫癎损伤”中的神经保护作用及“针药结合”治疗癫癎提供了有效依据。
Epilepasy are a kind of common diseases in the nervous system, it is incidence rate for 0.5-2% in the crowd. Currently, although research of epilepsy obtain certain make progress, for etiopathogenisis and pathogenesis of epilepsy currently still is not complete clear. A great deal of of the data manifestation, epilepsy and infalammatory reaction of central nervous system (CNS) relation close, inflammatory reaction come to a decision epilepsy to some extent of occurrence, development. Valid of inhibit inflammatory reaction in brain, result in changing the excitability of the neuron, attain the purpose of the anti-epileptic. But microglia play a critical role in the inflammatory reaction of CNS, activated microglia may secrete a number inflammatory factors, and the expression of CD40 be a key that inflammatory reaction. CD40 is a member of the tumor necrosis factor (TNF) receptor family. It interaction with CD40L which is the cognate ligand of CD40 leads to microglia secretion of cytokine and mediators of inflammation, and mediated inflammatory reaction. However, the CD40 mediated inflammatoory reaction whether also occurenc in epilepticus inflammatory pathology change? Currently, the related research temporary having no this aspect.
The acupuncture is an importance in the motherland medical science of non- medicine therapy, it at domestic and international already creation graveness influence. Study displayied, the acupuncture may influence inflammatory reaction by different mechanism, and adjust to release of cytokine and mediators of inflammation. Meanwhile, our study groups previously reported that electric acupuncture (EA) may available inhibited spontaneous recurrent seizure(SRS) through stimulus“baihui”and“dazhui”in the lithium pilocarpine-induced epileptic model. However, this function of EA, whether relation it regulate inflammatory reaction after seizure? This the demand be further study. Moreover, data have displaied that carbamazepine (CBZ) as the anti-epileptic drug (AEDs) have to inhibit inflammatory reaction and neuroprotective function. It not only can inhibit epileptic seizure, but also can influence inflammatory reaction process through different mechanism, alleviate clinical symptom that inflammatory reaction's cause. However, oxcarbazepine as be derivative of carbamazepine, it whether also same have the anti- inflammation function? Whether it possess brain protection function through amelioration inflammatory reaction after seizure? Currently, domestic and international didn't yet the related research of this aspect.
Aim at the above-mentioned problem, this topic choose to use the lithium pilocarpine-induced epileptic model, then through immunohistochemistry, Western blot, and ELISA etc, respectively. Firstly, observation microglia change and CD40 expression after status epilepticus (SE) in the experimental epileptic rat. Then, we carry on an intervention to the the epileptic rat through stimulating“bai hui”and“da zhui”two acupuncture points and administration OXC, and observation EA or OXC influence on CD40 mediated inflammation after SE, and two carry on contrast research. Secondly, we have observated EA or OXC intervention to influence of hippocampal neuronal injury after SE in the rat by Nissl staining. End, we further observation EA or OXC intervention to influence of SE and SRS in the rat.
Main research's result is as follows:
(1) Microglia propagating and activating,and CD40 expression increasing in the different areas of hippocampus after SE. And CD40 expression increase on the activated microglia, but no observation CD40 expression on the astroglia.
(2) EA or OXC intervention dissimilarity degree inhibited proliferation and activating of microglia and CD40 expression in the hippocampus of rat, with OXC most is obvious.
(3) EA or OXC intervention inhibited TNF-αexpression in the hippocampus of rat, and inhibiting of OXC the function is strong at the EA stimulate.
(4) EA or OXC intervention improved neuronal loss of hippocampus after SE, with CA1 area most is obivous, and neuroprotective of OXC is strong at the EA stimulate.
(5) EA or OXC intervention not influence development of SE, but they dissimilarity degree extended latency of SRS, and decreased frequency of SRS. In summary, this study demonstrats for the first time that CD40 expression hippocampus in the experimental epileptic rat.This results have showed that CD40-mediated inflammatory reaction occurs in epileptic pathology change. Meanwhile, carrying on EA or OXC intervention may inhibited CD40 mediated inflammatory reaction after SE. Whereafter, our experiment also confirmed EA and OXC possess effects which may protect brain and inhibit SRS.This results showed that EA and OXC may improve neuronal loss of hippocampus through inhibiting CD40 mediated inflammatory reaction, and influence development of SRS, eventually. Therefore, this study not only provided theories foundation and experiment data for EA treatment of epilepsy,but also provided valid basis for studying neuroprotecive effects of AEDs in the“epileptic brain”.Our data also provied evidence that“synchondrosis of EA and medicine”for treatment of epilepsy.
针刺疗法是祖国医学中重要的非药物疗法,其在国内外已产生重大影响。研究显示,针刺可通过不同的机制影响炎症反应,调控炎性因子及炎症介质的释放。同时,本课题组在前期的研究显示,在锂-匹罗卡品癫癎模型中,通过电针刺激“大椎”和“百会”二穴位可有效地抑制自发性再发作(SRS)。但是,电针的这一作用,是否和针刺调节癫癎发作后的炎症反应有关?这需要进一步探讨。另外,资料显示,抗癫癎药(AEDs)-卡马西平(Carbamazepine,CBZ)具有抑制炎症反应和神经保护的作用。其不但能够抑制癫癎发作,而且可通过不同机制影响炎症反应过程,缓解炎症反应引起的临床症状。但是,奥卡西平(Oxcarbazepine,OXC)作为CBZ的衍生物,是否也同样具有抗炎作用?是否可通过减轻癫癎发作后的炎症反应而起到脑保护作用?目前,国内外还没有此方面的相关研究。
针对上述问题,本课题选用锂-匹罗卡品癫癎模型,通过免疫组化、Western blot、ELISA等实验方法。首先观察了实验性癫癎大鼠在癫癎持续状态(status epilepticus,SE)后MG,CD40的表达及变化。随后我们通过对癫癎大鼠给予电针刺激“大椎”和“百会”二穴位和OXC的干预,来观察电针或OXC对SE后CD40介导的炎症反应的影响,并且对二者进行对比研究。其次,我们通过Nissl染色等方法观察了电针或OXC干预对SE后大鼠海马神经元损伤的影响。最后,我们进一步观察了电针或OXC干预对SE、SRS的影响。
主要研究结果如下:
(1)SE后大鼠海马不同区域MG增殖、激活,CD40表达增加,并且在激活的MG上CD40表达明显增加,而CD40在星型胶质细胞上未表达。
(2)电针或OXC干预不同程度抑制了SE后大鼠海马MG的增殖、激活及CD40的表达,以OXC最为明显。
(3)电针或OXC干预抑制了SE后大鼠海马TNF-α的表达,并且OXC的抑制作用强于电针刺激。
(4)电针或OXC干预改善了SE后海马神经元的缺失,以CA1区最为显著,OXC的保护作用强于电针刺激。
(5)电针或OXC干预对SE的发生、发展没有影响,但是二者不同程度延长了SRS的潜伏期、减少SRS的发作频率。
综上所述,本课题首次研究了CD40在实验性癫癎大鼠海马的表达,提示CD40介导的炎症反应存在于癫癎的炎症病理损伤机制中;同时,对癫癎大鼠进行电针或OXC干预可不同程度的抑制CD40介导的炎症反应,随后的实验也证实二者具有脑保护和抑制SRS的作用,提示电针或OXC可通过抑制CD40介导的炎症反应而改善海马神经元的损伤,最终影响SRS的发生、发展。因此,本研究不仅为电针治疗癫癎提供了理论基础和实验资料,而且为研究AEDs在“癫癎损伤”中的神经保护作用及“针药结合”治疗癫癎提供了有效依据。
Epilepasy are a kind of common diseases in the nervous system, it is incidence rate for 0.5-2% in the crowd. Currently, although research of epilepsy obtain certain make progress, for etiopathogenisis and pathogenesis of epilepsy currently still is not complete clear. A great deal of of the data manifestation, epilepsy and infalammatory reaction of central nervous system (CNS) relation close, inflammatory reaction come to a decision epilepsy to some extent of occurrence, development. Valid of inhibit inflammatory reaction in brain, result in changing the excitability of the neuron, attain the purpose of the anti-epileptic. But microglia play a critical role in the inflammatory reaction of CNS, activated microglia may secrete a number inflammatory factors, and the expression of CD40 be a key that inflammatory reaction. CD40 is a member of the tumor necrosis factor (TNF) receptor family. It interaction with CD40L which is the cognate ligand of CD40 leads to microglia secretion of cytokine and mediators of inflammation, and mediated inflammatory reaction. However, the CD40 mediated inflammatoory reaction whether also occurenc in epilepticus inflammatory pathology change? Currently, the related research temporary having no this aspect.
The acupuncture is an importance in the motherland medical science of non- medicine therapy, it at domestic and international already creation graveness influence. Study displayied, the acupuncture may influence inflammatory reaction by different mechanism, and adjust to release of cytokine and mediators of inflammation. Meanwhile, our study groups previously reported that electric acupuncture (EA) may available inhibited spontaneous recurrent seizure(SRS) through stimulus“baihui”and“dazhui”in the lithium pilocarpine-induced epileptic model. However, this function of EA, whether relation it regulate inflammatory reaction after seizure? This the demand be further study. Moreover, data have displaied that carbamazepine (CBZ) as the anti-epileptic drug (AEDs) have to inhibit inflammatory reaction and neuroprotective function. It not only can inhibit epileptic seizure, but also can influence inflammatory reaction process through different mechanism, alleviate clinical symptom that inflammatory reaction's cause. However, oxcarbazepine as be derivative of carbamazepine, it whether also same have the anti- inflammation function? Whether it possess brain protection function through amelioration inflammatory reaction after seizure? Currently, domestic and international didn't yet the related research of this aspect.
Aim at the above-mentioned problem, this topic choose to use the lithium pilocarpine-induced epileptic model, then through immunohistochemistry, Western blot, and ELISA etc, respectively. Firstly, observation microglia change and CD40 expression after status epilepticus (SE) in the experimental epileptic rat. Then, we carry on an intervention to the the epileptic rat through stimulating“bai hui”and“da zhui”two acupuncture points and administration OXC, and observation EA or OXC influence on CD40 mediated inflammation after SE, and two carry on contrast research. Secondly, we have observated EA or OXC intervention to influence of hippocampal neuronal injury after SE in the rat by Nissl staining. End, we further observation EA or OXC intervention to influence of SE and SRS in the rat.
Main research's result is as follows:
(1) Microglia propagating and activating,and CD40 expression increasing in the different areas of hippocampus after SE. And CD40 expression increase on the activated microglia, but no observation CD40 expression on the astroglia.
(2) EA or OXC intervention dissimilarity degree inhibited proliferation and activating of microglia and CD40 expression in the hippocampus of rat, with OXC most is obvious.
(3) EA or OXC intervention inhibited TNF-αexpression in the hippocampus of rat, and inhibiting of OXC the function is strong at the EA stimulate.
(4) EA or OXC intervention improved neuronal loss of hippocampus after SE, with CA1 area most is obivous, and neuroprotective of OXC is strong at the EA stimulate.
(5) EA or OXC intervention not influence development of SE, but they dissimilarity degree extended latency of SRS, and decreased frequency of SRS. In summary, this study demonstrats for the first time that CD40 expression hippocampus in the experimental epileptic rat.This results have showed that CD40-mediated inflammatory reaction occurs in epileptic pathology change. Meanwhile, carrying on EA or OXC intervention may inhibited CD40 mediated inflammatory reaction after SE. Whereafter, our experiment also confirmed EA and OXC possess effects which may protect brain and inhibit SRS.This results showed that EA and OXC may improve neuronal loss of hippocampus through inhibiting CD40 mediated inflammatory reaction, and influence development of SRS, eventually. Therefore, this study not only provided theories foundation and experiment data for EA treatment of epilepsy,but also provided valid basis for studying neuroprotecive effects of AEDs in the“epileptic brain”.Our data also provied evidence that“synchondrosis of EA and medicine”for treatment of epilepsy.
引文
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