Nesfatin-1对多巴胺能神经元的保护作用及机制探讨
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摘要
帕金森病(Parkinson's disease, PD)是多发于中老年的神经系统退行性疾病,主要病理改变是中脑黑质(substantia nigra, SN)致密带多巴胺(dopamine, DA)能神经元退行性变,从而导致纹状体(striatum, Str)释放的DA减少所致。虽然遗传、环境、氧化应激、细胞凋亡、炎症反应、蛋白质异常聚集等因素均参与PD的发病,但其确切病因尚不清楚。目前PD病人DA能神经元的保护性治疗途径主要包括铁离子去除途径、单胺氧化酶-B抑制途径、神经营养因子补充、抗氧化剂的应用、神经移植、神经节苷脂途径等,但尚无行之有效的治疗办法可以阻止或者延缓DA能神经元的退行性变。因此,深入探讨PD的发病机制,针对PD病因筛选研发更有效的天然或人工合成药物成为PD研究的关键问题之一
Nesfatin-1是2006年发现的一种由82个氨基酸组成的脑肠肽,由胃底的X/A样细胞分泌,其主要功能是抑制摄食和参与能量代谢,新近研究发现它也可以参与调节生殖、应激反应、认知等过程,并与抑郁和焦虑、癫痫的发病有关。目前有研究发现nesfatin-1在大鼠蛛网膜下腔出血和脑外伤中通过抗凋亡机制发挥神经保护作用。由于其与脑肠肽ghrelin都由胃底的X/A样细胞分泌,本课题组的前期研究工作已证实ghrelin对DA能神经元具有神经保护作用,那么,nesfatin-1对DA能神经元是否具有同样的保护作用?为了探讨这一问题,在1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin, MPTP)制备的亚急性PD小鼠模型上,通过高效液相色谱(high performance liquid chromatography, HPLC)检测了DA及其代谢产物的含量,免疫组织化学和免疫荧光技术观察了DA能神经元及其神经末梢的改变,蛋白免疫印迹法检测了SN区酪氨酸羟化酶(tyrosine hydroxylase, TH)含量的改变,观察了nesfatin-1对DA能神经元的保护作用。并进一步在体外培养的DA能细胞系——MES23.5细胞上,应用1-甲基-4-苯基吡啶阳离子(1-methyl-4-phenylpyridillium ion, MPP+)制备PD的细胞模型,通过3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(3-(4,5)-dimethylthiahiazo (-z-yl)-3,5-di-phenytetrazoliumromide, MTT)法检测细胞存活率,流式细胞术检测线粒体跨膜电位差(mitochondrial transmembrane potential,△ΨM)和caspase-3活性的变化,werstern blot法检测细胞色素C (cytochrome C, Cyt C)含量及细胞外调节蛋白激酶(extracellular regulated protein kinases, ERK1/2)磷酸化的变化,细胞免疫化学检测细胞核形态学改变,来深入探讨nesfatin-1神经保护作用的机制。结果如下：
1.在MPTP制备的亚急性PD模型小鼠中,Str内DA及其代谢产物二羟基苯乙酸(dihydroxyphenylacetic acid, DOPAC)和高香草酸(homovanillic acid, HVA)的含量均降低,分别降低96.61%、85.51%和97.2%(P<0.05)。100ng/μL和200ng/μL nesfatin-1预处理后,可拮抗由MPTP导致的DA、DOPAC和HVA含量的下降；400ng/μL nesfatin-1预处理后,可拮抗MPTP导致的DA和HVA含量的下降(P<0.05)。
2.在MPTP制备的亚急性PD模型小鼠中,SN区内TH免疫阳性细胞数目减少30%,TH蛋白表达下降37%,与对照组相比,差别有统计学意义(P<0.05),同时Str区TH免疫阳性神经纤维末梢减少。100ng/μL,200ng/μL,400ng/μL nesfatin-1预处理可拮抗MPTP造成的DA能神经元损伤,TH免疫阳性神经元数目分别恢复至正常对照组的100%,82%,80%(P<0.05),TH蛋白表达分别恢复至正常对照组的100%,98%,95%(P<0.05),Str区TH免疫阳性神经纤维末梢增多。
3. MPP+(300μmol/L)孵育MES23.5细胞24小时后,细胞存活率降低至对照组的74.82%,与对照组相比,差别有高度统计学意义(P<0.01)。不同浓度的nesfatin-1(10-7～10-13mol/L)预孵育后,可拮抗MPP+引起的细胞存活率的降低,分别为对照组的101.54%、114.39%、120.78%、110.45%、107.15%、107.78%和101.68%。10^9mol/L nesfatin-1的作用最明显。
4. MPP+(300μmol/L)孵育MES23.5细胞24小时后,细胞ΔΨM出现降低(P<0.05),而nesfatin-1(10-8和10-9mol/L)预处理后,可拮抗MPP+造成的ΔΨM的下降(P<0.05),10-9mol/L nesfatin-1的作用最明显。
5. MPP+(300μmol/L)孵育MES23.5细胞24小时后,细胞线粒体内Cyt C的含量降低,而胞浆中Cyt C含量升高(P<0.05)。10-9mol/L nesfatin-1预处理后,可拮抗MPP+造成的Cyt C从线粒体至细胞浆的释放(P<0.05)。
6. MPP+(300μmol/L)孵育MES23.5细胞24小时后,能够导致凋亡效应酶caspase-3的激活,caspase-3的活性为对照组的174.78%(P<0.05).10-9mol/L nesfatin-1预处理后,可以拮抗MPP+诱发的caspase-3的激活(P<0.05)。
7. MPP+(300μmol/L)孵育MES23.5细胞24小时后,细胞出现核的固缩、深染、破裂等凋亡现象,10-9mol/L nesfatin-1预孵育后,上述现象消失。
8.10-9mol/L nesfatin-1预孵育MES23.5细胞能够诱导ERK1/2蛋白磷酸化,30min达到高峰。尽管ERK1/2/MAPK磷酸化的阻滞剂PD98059预孵育30min,能够拮抗nesfatin-1诱导的ERKl/2磷酸化,但不能改变nesfatin-1拮抗MPP+诱导的ΔΨM下降和caspase-3激活的作用。
上述结果表明,nesfatin-1对MPTP和MPP+所致的DA能神经元的损伤均有保护作用,其机制可能是通过保护线粒体功能,抑制Cyt C的释放,进一步抑制caspase-3的激活而发挥,而这种保护作用与ERK1/2/MAPK信号通路无关。Nesfaitn-1可以通过抗凋亡功能而发挥对DA能神经元的保护作用,为PD的预防和治疗提供了新的策略,也为探讨nesfatin-1在中枢神经系统的生理作用提供了新的依据。
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive motor dysfunction. The key neuropathological features of PD are the loss of dopaminergic neurons in the substantia nigra (SN) and thus dopamine depletion in the striatum. However, the precise mechanisms leading to neurodegeneration in PD are not known, which genetic and environment factors are all involved. Up to now, there is no effective treatment for preventing or slowing the progression of neurodegeneration of dopaminergic neurons in the SN. Therefore, it is of great importance to investigate the etiology of PD and search for effective drugs to treat and prevent PD.
Nesfatin-1, a newly discovered82-amino-acid neuropeptide released by X/A like endocrine cells in the gastric glands, regulates food intake, energy homeostasis, reproductive processes, stress response, cognition. It is also related to depression, anxiety, and epilepsy. The recent studies that it could display neuroprotective effects in subarachnoid hemorrhage and brain injury seem particularly intriguing. However, the protective effect of nesfatin-1on dopaminergic neurons has not been elucidated. In the present study,1-methyl-4-phenyl-1,2,3,6-tetrahydropyridi (MPTP)-treated mice and1-methyl-4-phenylpyridillium ion (MPP+)-treated MES23.5dopaminergic cells were selected as PD models to investigate the protective effect of nesfatin-1on dopaminergic neurons and to elucidate its underlying mechanisms. To investigate the effects of nesfatin-1on MPTP-induced toxicity in PD mice, the number of tyrosine hydroxylase (TH) positive neurons, TH levels in SN, dopamine and its metabolites contents, TH immunoreactive fibers in the striatum (Str) were tested by immunofluorescence, western blot, high-performance liquid chromatograph (HPLC), immunohistochemistry, respectively. Further studies were conducted to detect the effect of nesfatin-1on the changes of cell viability, the mitochondrial transmembrane potential (△ΨM), caspase-3levels and cytochrome c (Cyt C) release in MPP+-treated MES23.5cells. Nesfatin-1could induce the phosphorylation of extracellular regulated protein kinases (ERK1/2), which could be abolished by its inhibitor PD98059. The effects of nesfatin-1could not be abolished by PD98059. The results are as follows:
1. The contents of DA, DOPAC and HVA in MPTP-treated mice were observed decreased compared with control group (P<0.05). Pretreatment with nesfatin-1(100ng/μL and200ng/μL), it could antagonize MPTP-induced reduction in the contents of DA, DOPAC and HVA (P<0.05). In400ng/μL nesfatin-1pretreatment group, only DA and HVA contents could be observed increased (P <0.05).
2. In MPTP-treated mice, reduction in the number of TH-positive neurons, TH protein levels in the SN and TH immunoreactive fibers in the Str were observed compared with that of control (P<0.05). Nesfatin-1(100ng/μL,200ng/μL and400ng/μL) pretreatment significantly abolished these effects (P<0.05).
3. MPP+(300μmol/L) could induce the reduction in cell viability in MES23.5cells (P<0.01). Pre-incubated with nesfatin-1(10-13to10-7mol/L) could antagonize MPP+-induced reduction in cell viability.
4. MPP+(300μmol/L) treatment resulted in△Ψm decrease assessed by flow cytometry after24h exposure in MES23.5cells. Pre-incubation with nesfatin-1(10-8and10-9mol/L) could abolish this effect.
5. Cyt C levels were observed decreased in the mitochondrion and increased in the cytosol after MPP+treatment.10-9mol/L nesfatin-1pretreatment significant antagonized Cyt C release from the mitochondrion to cytosol induced by MPP+(P<0.05).
6. MPP+(300μmol/L) treatment induced easpase-3activation. This effect could be abolished by nesfatin-1pretreatment (P<0.05).
7. MPP+(300μmol/L) treatment could induce hypercondensed, broken and anachromasis of nuclei in MES23.5cells.10-9mol/L nesfatin-1pretreatment attenuated the morphological changes of these cells.
8. Nesfatin-1could induced phosphorylation of ERK1/2which reached its peak at30min and could be abolished by ERK/MAPK inhibitors PD98059. PD98059(10μmol/L) could not abolish the effects of nesfatin-1on the decrease of△ΨM and caspase-3activation induced by MPP+.
The results indicate that nesfatin-1has neuroprotective effect in PD models both in vivo and in vitro. The underlying mechanism might be related to prevent mitochondrion damage by inhibiting Cyt C release from mitochondrion and subsequent caspase3-mediated apoptosis cascades of cells. The anti-apoptotic action of nesfatin-1is independent of ERK1/2/MAPK pathway. This work provides new evidences to explore the possible use of nesfatin-1as a potential therapeutic drug in PD by its anti-apoptotic property.
Nesfatin-1是2006年发现的一种由82个氨基酸组成的脑肠肽,由胃底的X/A样细胞分泌,其主要功能是抑制摄食和参与能量代谢,新近研究发现它也可以参与调节生殖、应激反应、认知等过程,并与抑郁和焦虑、癫痫的发病有关。目前有研究发现nesfatin-1在大鼠蛛网膜下腔出血和脑外伤中通过抗凋亡机制发挥神经保护作用。由于其与脑肠肽ghrelin都由胃底的X/A样细胞分泌,本课题组的前期研究工作已证实ghrelin对DA能神经元具有神经保护作用,那么,nesfatin-1对DA能神经元是否具有同样的保护作用?为了探讨这一问题,在1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridin, MPTP)制备的亚急性PD小鼠模型上,通过高效液相色谱(high performance liquid chromatography, HPLC)检测了DA及其代谢产物的含量,免疫组织化学和免疫荧光技术观察了DA能神经元及其神经末梢的改变,蛋白免疫印迹法检测了SN区酪氨酸羟化酶(tyrosine hydroxylase, TH)含量的改变,观察了nesfatin-1对DA能神经元的保护作用。并进一步在体外培养的DA能细胞系——MES23.5细胞上,应用1-甲基-4-苯基吡啶阳离子(1-methyl-4-phenylpyridillium ion, MPP+)制备PD的细胞模型,通过3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐(3-(4,5)-dimethylthiahiazo (-z-yl)-3,5-di-phenytetrazoliumromide, MTT)法检测细胞存活率,流式细胞术检测线粒体跨膜电位差(mitochondrial transmembrane potential,△ΨM)和caspase-3活性的变化,werstern blot法检测细胞色素C (cytochrome C, Cyt C)含量及细胞外调节蛋白激酶(extracellular regulated protein kinases, ERK1/2)磷酸化的变化,细胞免疫化学检测细胞核形态学改变,来深入探讨nesfatin-1神经保护作用的机制。结果如下：
1.在MPTP制备的亚急性PD模型小鼠中,Str内DA及其代谢产物二羟基苯乙酸(dihydroxyphenylacetic acid, DOPAC)和高香草酸(homovanillic acid, HVA)的含量均降低,分别降低96.61%、85.51%和97.2%(P<0.05)。100ng/μL和200ng/μL nesfatin-1预处理后,可拮抗由MPTP导致的DA、DOPAC和HVA含量的下降；400ng/μL nesfatin-1预处理后,可拮抗MPTP导致的DA和HVA含量的下降(P<0.05)。
2.在MPTP制备的亚急性PD模型小鼠中,SN区内TH免疫阳性细胞数目减少30%,TH蛋白表达下降37%,与对照组相比,差别有统计学意义(P<0.05),同时Str区TH免疫阳性神经纤维末梢减少。100ng/μL,200ng/μL,400ng/μL nesfatin-1预处理可拮抗MPTP造成的DA能神经元损伤,TH免疫阳性神经元数目分别恢复至正常对照组的100%,82%,80%(P<0.05),TH蛋白表达分别恢复至正常对照组的100%,98%,95%(P<0.05),Str区TH免疫阳性神经纤维末梢增多。
3. MPP+(300μmol/L)孵育MES23.5细胞24小时后,细胞存活率降低至对照组的74.82%,与对照组相比,差别有高度统计学意义(P<0.01)。不同浓度的nesfatin-1(10-7～10-13mol/L)预孵育后,可拮抗MPP+引起的细胞存活率的降低,分别为对照组的101.54%、114.39%、120.78%、110.45%、107.15%、107.78%和101.68%。10^9mol/L nesfatin-1的作用最明显。
4. MPP+(300μmol/L)孵育MES23.5细胞24小时后,细胞ΔΨM出现降低(P<0.05),而nesfatin-1(10-8和10-9mol/L)预处理后,可拮抗MPP+造成的ΔΨM的下降(P<0.05),10-9mol/L nesfatin-1的作用最明显。
5. MPP+(300μmol/L)孵育MES23.5细胞24小时后,细胞线粒体内Cyt C的含量降低,而胞浆中Cyt C含量升高(P<0.05)。10-9mol/L nesfatin-1预处理后,可拮抗MPP+造成的Cyt C从线粒体至细胞浆的释放(P<0.05)。
6. MPP+(300μmol/L)孵育MES23.5细胞24小时后,能够导致凋亡效应酶caspase-3的激活,caspase-3的活性为对照组的174.78%(P<0.05).10-9mol/L nesfatin-1预处理后,可以拮抗MPP+诱发的caspase-3的激活(P<0.05)。
7. MPP+(300μmol/L)孵育MES23.5细胞24小时后,细胞出现核的固缩、深染、破裂等凋亡现象,10-9mol/L nesfatin-1预孵育后,上述现象消失。
8.10-9mol/L nesfatin-1预孵育MES23.5细胞能够诱导ERK1/2蛋白磷酸化,30min达到高峰。尽管ERK1/2/MAPK磷酸化的阻滞剂PD98059预孵育30min,能够拮抗nesfatin-1诱导的ERKl/2磷酸化,但不能改变nesfatin-1拮抗MPP+诱导的ΔΨM下降和caspase-3激活的作用。
上述结果表明,nesfatin-1对MPTP和MPP+所致的DA能神经元的损伤均有保护作用,其机制可能是通过保护线粒体功能,抑制Cyt C的释放,进一步抑制caspase-3的激活而发挥,而这种保护作用与ERK1/2/MAPK信号通路无关。Nesfaitn-1可以通过抗凋亡功能而发挥对DA能神经元的保护作用,为PD的预防和治疗提供了新的策略,也为探讨nesfatin-1在中枢神经系统的生理作用提供了新的依据。
Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive motor dysfunction. The key neuropathological features of PD are the loss of dopaminergic neurons in the substantia nigra (SN) and thus dopamine depletion in the striatum. However, the precise mechanisms leading to neurodegeneration in PD are not known, which genetic and environment factors are all involved. Up to now, there is no effective treatment for preventing or slowing the progression of neurodegeneration of dopaminergic neurons in the SN. Therefore, it is of great importance to investigate the etiology of PD and search for effective drugs to treat and prevent PD.
Nesfatin-1, a newly discovered82-amino-acid neuropeptide released by X/A like endocrine cells in the gastric glands, regulates food intake, energy homeostasis, reproductive processes, stress response, cognition. It is also related to depression, anxiety, and epilepsy. The recent studies that it could display neuroprotective effects in subarachnoid hemorrhage and brain injury seem particularly intriguing. However, the protective effect of nesfatin-1on dopaminergic neurons has not been elucidated. In the present study,1-methyl-4-phenyl-1,2,3,6-tetrahydropyridi (MPTP)-treated mice and1-methyl-4-phenylpyridillium ion (MPP+)-treated MES23.5dopaminergic cells were selected as PD models to investigate the protective effect of nesfatin-1on dopaminergic neurons and to elucidate its underlying mechanisms. To investigate the effects of nesfatin-1on MPTP-induced toxicity in PD mice, the number of tyrosine hydroxylase (TH) positive neurons, TH levels in SN, dopamine and its metabolites contents, TH immunoreactive fibers in the striatum (Str) were tested by immunofluorescence, western blot, high-performance liquid chromatograph (HPLC), immunohistochemistry, respectively. Further studies were conducted to detect the effect of nesfatin-1on the changes of cell viability, the mitochondrial transmembrane potential (△ΨM), caspase-3levels and cytochrome c (Cyt C) release in MPP+-treated MES23.5cells. Nesfatin-1could induce the phosphorylation of extracellular regulated protein kinases (ERK1/2), which could be abolished by its inhibitor PD98059. The effects of nesfatin-1could not be abolished by PD98059. The results are as follows:
1. The contents of DA, DOPAC and HVA in MPTP-treated mice were observed decreased compared with control group (P<0.05). Pretreatment with nesfatin-1(100ng/μL and200ng/μL), it could antagonize MPTP-induced reduction in the contents of DA, DOPAC and HVA (P<0.05). In400ng/μL nesfatin-1pretreatment group, only DA and HVA contents could be observed increased (P <0.05).
2. In MPTP-treated mice, reduction in the number of TH-positive neurons, TH protein levels in the SN and TH immunoreactive fibers in the Str were observed compared with that of control (P<0.05). Nesfatin-1(100ng/μL,200ng/μL and400ng/μL) pretreatment significantly abolished these effects (P<0.05).
3. MPP+(300μmol/L) could induce the reduction in cell viability in MES23.5cells (P<0.01). Pre-incubated with nesfatin-1(10-13to10-7mol/L) could antagonize MPP+-induced reduction in cell viability.
4. MPP+(300μmol/L) treatment resulted in△Ψm decrease assessed by flow cytometry after24h exposure in MES23.5cells. Pre-incubation with nesfatin-1(10-8and10-9mol/L) could abolish this effect.
5. Cyt C levels were observed decreased in the mitochondrion and increased in the cytosol after MPP+treatment.10-9mol/L nesfatin-1pretreatment significant antagonized Cyt C release from the mitochondrion to cytosol induced by MPP+(P<0.05).
6. MPP+(300μmol/L) treatment induced easpase-3activation. This effect could be abolished by nesfatin-1pretreatment (P<0.05).
7. MPP+(300μmol/L) treatment could induce hypercondensed, broken and anachromasis of nuclei in MES23.5cells.10-9mol/L nesfatin-1pretreatment attenuated the morphological changes of these cells.
8. Nesfatin-1could induced phosphorylation of ERK1/2which reached its peak at30min and could be abolished by ERK/MAPK inhibitors PD98059. PD98059(10μmol/L) could not abolish the effects of nesfatin-1on the decrease of△ΨM and caspase-3activation induced by MPP+.
The results indicate that nesfatin-1has neuroprotective effect in PD models both in vivo and in vitro. The underlying mechanism might be related to prevent mitochondrion damage by inhibiting Cyt C release from mitochondrion and subsequent caspase3-mediated apoptosis cascades of cells. The anti-apoptotic action of nesfatin-1is independent of ERK1/2/MAPK pathway. This work provides new evidences to explore the possible use of nesfatin-1as a potential therapeutic drug in PD by its anti-apoptotic property.
引文
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