尼莫地平和梓醇的神经保护作用
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摘要
胶质细胞,中枢神经系统最丰富的细胞,被认为在中枢神经系统中起提供营养与支持,维持微环境,形成髓鞘,免疫监视和调节神经递质的作用。近来研究发现,胶质细胞还参与一系列中枢神经系统疾病,包括脑缺血和帕金森症等神经系统退行性疾病,并在这些疾病的发展过程中起重要的作用。本研究以LPS诱导大鼠中脑神经-胶质细胞混合培养体系中多巴胺神经元脱失为炎症介导的PD模型,以原代培养的星形胶质细胞氧糖剥夺-再复氧为体外缺血模型,探讨了尼莫地平和梓醇的神经保护作用。
1.尼莫地平对炎症介导的多巴胺神经元退化的保护作用
人们逐渐认识到脑内炎症反应在多种神经退行性疾病包括帕金森病和阿茨海默症中起着重要作用。炎症介导的神经退化与脑内在免疫细胞——小胶质细胞激活有关。激活的小胶质细胞产生前炎症因子和神经毒因子,包括细胞因子、活性氧自由基、一氧化氮和花生四烯酸代谢产物等,它们诱导神经元退化。因此,识别抑制小胶质细胞激活的化合物,有可能开发出治疗炎症调节的神经退行性疾病的药物。本研究应用中脑神经.胶质细胞混合培养体系,报道了尼莫地平,一种用于治疗心血管疾病的钙离子通道阻断剂,以剂量依赖的方式显著地阻止了LPS诱导的多巴胺神经元的变性。利用神经和胶质细胞重组培养,发现尼莫地平只有在小胶质细胞存在下,才能发挥其神经保护作用。此外,在去除小胶质细胞后的大鼠中脑神经.胶质细胞混合培养体系中,尼莫地平不能降低MPP~+诱导的神经毒性,提示尼莫地平对神经元直接损伤无保护作用。由于尼莫地平显著抑制LPS诱导的小胶质细胞生成一氧化氮(NO),肿瘤坏死因子-α(TNF-α),白介素-1β(IL-1β),花生四烯酸代谢产物.前列腺素E_2(PGE_2)和反应性氧自由基(reactive oxygenspecies,ROS),表明尼莫地平对LPS诱导的多巴胺神经元的变性的保护作用是通过抑制小胶质细胞激活实现的。进一步研究显示,尼莫地平不能阻止LPS诱导的烟酰胺腺嘌呤二核苷酸磷酸(β-nicotinamide adenine dinucleotide phosphate,NADPH)氧化酶(PHOX)缺陷小鼠(PHOX~(-/-))中的多巴胺神经元丢失,而明显地抑制LPS诱导的野生型小鼠(PHOX~(+/+))PHOX胞质亚基p47phox向细胞膜的转位和多巴胺神经元丢失。这些结果提示,尼莫地平通过抑制小胶质细胞调节的氧化应激和炎症反应,保护多巴胺神经元免于损伤。此外,我们的研究揭示了PHOX是尼莫地平一个新的作用位点。因此,尼莫地平可能是一个治疗炎症相关的神经退行性疾病如帕金森病的潜在药物。
2.梓醇对缺血诱导的星形胶质细胞损伤的保护作用
脑缺血(Brain ischemia)是一种由于脑供血不足造成不可逆脑损伤而引起的一种急性神经系统退行性疾病,人们对其病理机制和防治措施进行了大量的研究,研究注意力主要集中在神经元上,治疗的策略也是针对阻止神经元功能的丧失。然而,近年来人们发现,脑缺血时星形胶质细胞的功能状态决定着缺血神经元的发展和转归。梓醇是一种环烯醚萜甙类小分子化合物,为传统中药地黄(Rehmannia glutinosa)的主要有效成分。先前研究发现,梓醇能够阻止脑缺血.再灌注诱导的沙土鼠CA1海马神经损伤,对脑缺血.再灌注导致的学习记忆障碍有明显的改善作用。本研究我们探讨了梓醇在缺血-再灌注诱导的星形胶质细胞损伤中作用及其作用机制。以原代培养小鼠星形胶质细胞氧糖剥夺-再复氧为体外缺血模型,通过四甲基偶氮唑盐(3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyl-terazoliumbromide,MTT)比色分析,乳酸脱氢酶(lactate dehydrogenase,LDH)检测和形态观察,发现梓醇以剂量依赖的方式对缺血诱导的星形胶质细胞损伤具有明显的保护作用。此外,梓醇有效地阻止缺血引起的星形胶质细胞线粒体膜电位的降低,抑制活性氧自由基(reactive oxygen species,ROS)和一氧化氮(nitric oxide,NO)的生成,降低脂质过氧化物水平和诱导型一氧化氮合成酶(inducible nitric oxide synthase,iNOS)的活性,提高超氧化物歧化酶(superoxide dismutase,SOD)和谷胱甘肽过氧化物酶(glutathione peroxidase,GSH-Px)的活性,增加谷胱甘肽(glutathione,GSH)含量。这些结果提示梓醇通过抑制自由基生成,提高抗氧化能力,从而保护缺血.再灌注诱导的星形胶质细胞损伤。
Glial cells,the most abundant cell types in the central nervous system(CNS),have been believed to provide support and nutrition,maintain homeostasis,form myelin,serve immune surveillance,and modulate neurotransmission.Recent studies suggest that glial cells also are implicated in a wide range of CNS disorders including ischemia and Parkinson's disease(PD) neurodegenerative disease,and play an important role in the progress of disorders.In this study,the protective effects of nimodipine and catalpol on neurodegenerative disease were investigated with LPS-induced degeneration of dopaminergic neurons in mesencephalic neuron-glia cultures as a PD model and primary cultured astrocytes exposed to oxygen-glucose deprivation followed by reperfusion as an in vitro ischemic model.
1.Nimodipine protects dopaminergic neurons against inflammation-mediated degeneration through the inhibition of microglial activation
Inflammation in the brain has increasingly been recognized to play an important role in the pathogenesis of several neurodegenerative disorders,including Parkinson's disease and Alzheimer's disease.Inflammation-mediated neurodegeneration involves activation of the brain's resident immune cells,the microglia,which produce proinflammatory and neurotoxic factors,including cytokines,reactive oxygen intermediates,nitric oxide,and eicosanoids that impact on neurons to induce neurodegeneration.Hence,identification of compounds that prevent microglial activation may be highly desirable in the search for therapeutic agents for inflammation-mediated neurodegenerative diseases.In this study,nimodipine,a calcium channel blocker commonly-used in the therapy of cardiovascular diseases,was reported to significantly reduce lipopolysaccharide(LPS)-induced the degeneration of dopaminergic(DA) neurons in a dose-dependent manner in mesencephalic neuron-glia cultures.In addition,with reconstituted neuron and glia cultures,nimodipine was found to be neuroprotective only in the presence of microglia.Moreover,nimodipine was not neuroprotective to 1-methyi-4-phenylpyridinium (MPP~+)-induced DA neurotoxitity in the absence of microglia.The neuroprotective effect of nimodipine was attributed to the inhibition of microglial activation, since nimodipine significantly inhibited the production of nitric oxide(NO),tumor necrosis factor-α(TNF-α),intedeukin-1β(IL-1β) and prostaglandin E_2(PGE_2) from LPS-stimulated microglia.Mechanistic study showed that nimodipine failed to protect the degeneration of neurons in neuron-glia cultures from mice lacking functional NADPH oxidase(PHOX),a key enzyme for extracellular superoxide production in immune cells,and significantly reduced LPS-induced PHOX cytosolic subunit p47phox translocation to the cell membrane in microglia from wild-type mice(PHOX~(+/+)).These results suggest that nimodipine is protective to DA neurodegeneration via inhibiting the microglial-mediated oxidative stress and inflammatory response.Furthermore,our study revealed that inhibition of PHOX is a novel site of action for the calcium channel blocker-independent effect of nimodipine.Thus, nimodipine may be a potential therapeutic agent for the treatment of inflammation-related neurodegenerative disorders such as Parkinson's disease.
2.Catalpol protects primary cultured astrocytes from ischemia-induced damage in vitro
Brain ischemia is an acute neurodegenerative disease caused by insufficiency bloods supply to a particular brain area and subsequent of irreversible brain damage.Studies on pathomechanism of brain ischemia have mainly focused neurons and,accordingly,therapeutic strategies have been designed to counteract neuronal dysfunction.However,recent data indicate that a decrease in neuronal survival during and after ischemia is also associated with astrocytic dysfunction.Thus,counteracting astrocytic dysfunction during ischemia and reperfusion provide a new option of the pharmacological intervention in prevention of brain damage.Catalpol,an iridoid glycoside abundant in the roots of Rehmannia glutinosa,has been previously found to prevent the loss of CA1 hippocampal neurons and to reduce working errors in gerbils after ischemia-reperfusion injury.In the present study,we investigated the effects of catalpol on astrocytes in an ischemic model to further characterize its neuroprotective mechanisms.Primary cultured astrocytes exposed to oxygen-glucose deprivation(OGD) followed by reperfusion(adding back oxygen and glucose,OGD-R),were used as an in vitro ischemic model.Treatment of the astrocytes with catalpol during ischemia-reperfusion increased astrocyte survival significantly in a concentration-dependent manner,as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay,lactate dehydrogenase(LDH) release and morphological observation.In addition,catalpol prevented the decrease in mitochondrial membrane potential,inhibited the formation of reactive oxygen species(ROS) and the production of nitric oxide(NO), decreased the level of lipid peroxide and the activity of inducible nitric oxide synthase(iNOS), and elevated the activities of superoxide dismutase(SOD),glutathione peroxidase(GSH-Px) and the content of glutathione(GSH).These results suggest that catalpol exerts the most significant cytoprotective effect on astrocytes by suppressing the production of free radicals and elevating antioxidant capacity.
1.尼莫地平对炎症介导的多巴胺神经元退化的保护作用
人们逐渐认识到脑内炎症反应在多种神经退行性疾病包括帕金森病和阿茨海默症中起着重要作用。炎症介导的神经退化与脑内在免疫细胞——小胶质细胞激活有关。激活的小胶质细胞产生前炎症因子和神经毒因子,包括细胞因子、活性氧自由基、一氧化氮和花生四烯酸代谢产物等,它们诱导神经元退化。因此,识别抑制小胶质细胞激活的化合物,有可能开发出治疗炎症调节的神经退行性疾病的药物。本研究应用中脑神经.胶质细胞混合培养体系,报道了尼莫地平,一种用于治疗心血管疾病的钙离子通道阻断剂,以剂量依赖的方式显著地阻止了LPS诱导的多巴胺神经元的变性。利用神经和胶质细胞重组培养,发现尼莫地平只有在小胶质细胞存在下,才能发挥其神经保护作用。此外,在去除小胶质细胞后的大鼠中脑神经.胶质细胞混合培养体系中,尼莫地平不能降低MPP~+诱导的神经毒性,提示尼莫地平对神经元直接损伤无保护作用。由于尼莫地平显著抑制LPS诱导的小胶质细胞生成一氧化氮(NO),肿瘤坏死因子-α(TNF-α),白介素-1β(IL-1β),花生四烯酸代谢产物.前列腺素E_2(PGE_2)和反应性氧自由基(reactive oxygenspecies,ROS),表明尼莫地平对LPS诱导的多巴胺神经元的变性的保护作用是通过抑制小胶质细胞激活实现的。进一步研究显示,尼莫地平不能阻止LPS诱导的烟酰胺腺嘌呤二核苷酸磷酸(β-nicotinamide adenine dinucleotide phosphate,NADPH)氧化酶(PHOX)缺陷小鼠(PHOX~(-/-))中的多巴胺神经元丢失,而明显地抑制LPS诱导的野生型小鼠(PHOX~(+/+))PHOX胞质亚基p47phox向细胞膜的转位和多巴胺神经元丢失。这些结果提示,尼莫地平通过抑制小胶质细胞调节的氧化应激和炎症反应,保护多巴胺神经元免于损伤。此外,我们的研究揭示了PHOX是尼莫地平一个新的作用位点。因此,尼莫地平可能是一个治疗炎症相关的神经退行性疾病如帕金森病的潜在药物。
2.梓醇对缺血诱导的星形胶质细胞损伤的保护作用
脑缺血(Brain ischemia)是一种由于脑供血不足造成不可逆脑损伤而引起的一种急性神经系统退行性疾病,人们对其病理机制和防治措施进行了大量的研究,研究注意力主要集中在神经元上,治疗的策略也是针对阻止神经元功能的丧失。然而,近年来人们发现,脑缺血时星形胶质细胞的功能状态决定着缺血神经元的发展和转归。梓醇是一种环烯醚萜甙类小分子化合物,为传统中药地黄(Rehmannia glutinosa)的主要有效成分。先前研究发现,梓醇能够阻止脑缺血.再灌注诱导的沙土鼠CA1海马神经损伤,对脑缺血.再灌注导致的学习记忆障碍有明显的改善作用。本研究我们探讨了梓醇在缺血-再灌注诱导的星形胶质细胞损伤中作用及其作用机制。以原代培养小鼠星形胶质细胞氧糖剥夺-再复氧为体外缺血模型,通过四甲基偶氮唑盐(3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyl-terazoliumbromide,MTT)比色分析,乳酸脱氢酶(lactate dehydrogenase,LDH)检测和形态观察,发现梓醇以剂量依赖的方式对缺血诱导的星形胶质细胞损伤具有明显的保护作用。此外,梓醇有效地阻止缺血引起的星形胶质细胞线粒体膜电位的降低,抑制活性氧自由基(reactive oxygen species,ROS)和一氧化氮(nitric oxide,NO)的生成,降低脂质过氧化物水平和诱导型一氧化氮合成酶(inducible nitric oxide synthase,iNOS)的活性,提高超氧化物歧化酶(superoxide dismutase,SOD)和谷胱甘肽过氧化物酶(glutathione peroxidase,GSH-Px)的活性,增加谷胱甘肽(glutathione,GSH)含量。这些结果提示梓醇通过抑制自由基生成,提高抗氧化能力,从而保护缺血.再灌注诱导的星形胶质细胞损伤。
Glial cells,the most abundant cell types in the central nervous system(CNS),have been believed to provide support and nutrition,maintain homeostasis,form myelin,serve immune surveillance,and modulate neurotransmission.Recent studies suggest that glial cells also are implicated in a wide range of CNS disorders including ischemia and Parkinson's disease(PD) neurodegenerative disease,and play an important role in the progress of disorders.In this study,the protective effects of nimodipine and catalpol on neurodegenerative disease were investigated with LPS-induced degeneration of dopaminergic neurons in mesencephalic neuron-glia cultures as a PD model and primary cultured astrocytes exposed to oxygen-glucose deprivation followed by reperfusion as an in vitro ischemic model.
1.Nimodipine protects dopaminergic neurons against inflammation-mediated degeneration through the inhibition of microglial activation
Inflammation in the brain has increasingly been recognized to play an important role in the pathogenesis of several neurodegenerative disorders,including Parkinson's disease and Alzheimer's disease.Inflammation-mediated neurodegeneration involves activation of the brain's resident immune cells,the microglia,which produce proinflammatory and neurotoxic factors,including cytokines,reactive oxygen intermediates,nitric oxide,and eicosanoids that impact on neurons to induce neurodegeneration.Hence,identification of compounds that prevent microglial activation may be highly desirable in the search for therapeutic agents for inflammation-mediated neurodegenerative diseases.In this study,nimodipine,a calcium channel blocker commonly-used in the therapy of cardiovascular diseases,was reported to significantly reduce lipopolysaccharide(LPS)-induced the degeneration of dopaminergic(DA) neurons in a dose-dependent manner in mesencephalic neuron-glia cultures.In addition,with reconstituted neuron and glia cultures,nimodipine was found to be neuroprotective only in the presence of microglia.Moreover,nimodipine was not neuroprotective to 1-methyi-4-phenylpyridinium (MPP~+)-induced DA neurotoxitity in the absence of microglia.The neuroprotective effect of nimodipine was attributed to the inhibition of microglial activation, since nimodipine significantly inhibited the production of nitric oxide(NO),tumor necrosis factor-α(TNF-α),intedeukin-1β(IL-1β) and prostaglandin E_2(PGE_2) from LPS-stimulated microglia.Mechanistic study showed that nimodipine failed to protect the degeneration of neurons in neuron-glia cultures from mice lacking functional NADPH oxidase(PHOX),a key enzyme for extracellular superoxide production in immune cells,and significantly reduced LPS-induced PHOX cytosolic subunit p47phox translocation to the cell membrane in microglia from wild-type mice(PHOX~(+/+)).These results suggest that nimodipine is protective to DA neurodegeneration via inhibiting the microglial-mediated oxidative stress and inflammatory response.Furthermore,our study revealed that inhibition of PHOX is a novel site of action for the calcium channel blocker-independent effect of nimodipine.Thus, nimodipine may be a potential therapeutic agent for the treatment of inflammation-related neurodegenerative disorders such as Parkinson's disease.
2.Catalpol protects primary cultured astrocytes from ischemia-induced damage in vitro
Brain ischemia is an acute neurodegenerative disease caused by insufficiency bloods supply to a particular brain area and subsequent of irreversible brain damage.Studies on pathomechanism of brain ischemia have mainly focused neurons and,accordingly,therapeutic strategies have been designed to counteract neuronal dysfunction.However,recent data indicate that a decrease in neuronal survival during and after ischemia is also associated with astrocytic dysfunction.Thus,counteracting astrocytic dysfunction during ischemia and reperfusion provide a new option of the pharmacological intervention in prevention of brain damage.Catalpol,an iridoid glycoside abundant in the roots of Rehmannia glutinosa,has been previously found to prevent the loss of CA1 hippocampal neurons and to reduce working errors in gerbils after ischemia-reperfusion injury.In the present study,we investigated the effects of catalpol on astrocytes in an ischemic model to further characterize its neuroprotective mechanisms.Primary cultured astrocytes exposed to oxygen-glucose deprivation(OGD) followed by reperfusion(adding back oxygen and glucose,OGD-R),were used as an in vitro ischemic model.Treatment of the astrocytes with catalpol during ischemia-reperfusion increased astrocyte survival significantly in a concentration-dependent manner,as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay,lactate dehydrogenase(LDH) release and morphological observation.In addition,catalpol prevented the decrease in mitochondrial membrane potential,inhibited the formation of reactive oxygen species(ROS) and the production of nitric oxide(NO), decreased the level of lipid peroxide and the activity of inducible nitric oxide synthase(iNOS), and elevated the activities of superoxide dismutase(SOD),glutathione peroxidase(GSH-Px) and the content of glutathione(GSH).These results suggest that catalpol exerts the most significant cytoprotective effect on astrocytes by suppressing the production of free radicals and elevating antioxidant capacity.
引文
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