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Mechanisms and Prevention of Neurodegeneration via Microglial Activation in the Nigro-Striatal System

黑质纹状体系统中小胶质细胞激活导致神经退行性变的机制和预防

基本信息

批准号：
18590052
负责人：
KATSUKI Hiroshi
金额：
$ 2.55万
依托单位：
Kumamoto University (2007)Kyoto University (2006)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

This study addressed the mechanisms of microglia-mediated dopaminergic neurodegeneration as well as the effects of neuroprotective drugs expected to have novel pharmacodynamic actions. (1) Am80, a retinoid RAR agonist, inhibited dopaminergic neuron death induced by IFN- γ/LPS. Am80 increased the expression of BDNF mRNA in cultured midbrain tissues, and the protective effect of Am80 was reversed by a TrkB inhibitor and anti-BDNF neutralizing antibodies. BDNF, whose production is enhanced by RAR stimulation, is suggested to protect dopaminergic neurons in an autocrine / paracrine manner. (2) Resveratrol, an activator of sirtuin family of histone deacetylases, prevented dopaminergic neuron death induced by MPP+ and thrombin. However, the inhibitor of histone deacetylases did not affect the protective action of resveratrol. Resveratrol prevented the increase in the production of reactive oxygen species and the depletion of glutathione induced by MPP+, suggesting that antioxidative properties are involved in the protective effect of resveratrol. On the other hand, dopaminergic neuron death and enhanced p53 acetylation induced by DNA alkylating agents were inhibited by resveratrol and NAD, indicating that sirtuin-activating properties may be involved in neuroprotection under several circumstances. (3) IFN- γ/LPS, NO donors and a cyclic GMP analog all induced HO-1 expression in cultured midbrain tissues. HO-1 induction in dopaminergic neurons in response to IFN- γ/LPS was suppressed by a soluble guanylate cyclase (sGC) inhibitor. An HO-1 inhibitor and a sGC inhibitor exacerbated, whereas an HO-1 activator and a cyclic GMP analog prevented, dopaminergic neuron death induced by IFN-γ/LPS. The results suggest that induction of HO-1 expression via NO-cyclic GMP signaling pathway functions as an endogenous protective mechanism of dopaminergic neurons.

本研究探讨了小胶质细胞介导的多巴胺能神经变性的机制以及预期具有新药效学作用的神经保护药物的作用。(1)维甲酸RAR受体激动剂Am 80可抑制IFN- γ/LPS诱导的多巴胺能神经元死亡。Am 80可增加培养中脑组织中BDNF mRNA的表达，TrkB抑制剂和抗BDNF中和抗体可逆转Am 80的保护作用。BDNF，其生产增强RAR刺激，建议保护多巴胺能神经元的自分泌/旁分泌的方式。(2)白藜芦醇是组蛋白去乙酰化酶sirtuin家族的激活剂，可防止MPP+和凝血酶诱导的多巴胺能神经元死亡。然而，组蛋白去乙酰化酶抑制剂并不影响白藜芦醇的保护作用。白藜芦醇阻止MPP+诱导的活性氧产生和谷胱甘肽消耗的增加，表明白藜芦醇的保护作用涉及抗氧化特性。另一方面，多巴胺能神经元死亡和DNA烷化剂诱导的增强的p53乙酰化被白藜芦醇和NAD抑制，表明沉默调节蛋白激活特性可能在几种情况下参与神经保护。(3)IFN- γ/LPS、NO供体和环GMP类似物均可诱导培养中脑组织HO-1表达。可溶性鸟苷酸环化酶（sGC）抑制剂可抑制IFN- γ/LPS诱导的多巴胺能神经元HO-1表达。HO-1抑制剂和sGC抑制剂加剧了IFN-γ/LPS诱导的多巴胺能神经元死亡，而HO-1激活剂和环GMP类似物阻止了IFN-γ/LPS诱导的多巴胺能神经元死亡。提示NO-环GMP信号通路诱导HO-1表达可能是多巴胺能神经元的内源性保护机制。