Simvastatin inhibits the activation of p21ras and prevents the loss of dopaminergic neurons in a mouse model of Parkinson's disease.
Simvastatin inhibits the activation of p21ras and prevents the loss of dopaminergic neurons in a mouse model of Parkinson's disease.
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DOI：
10.1523/jneurosci.4144-09.2009
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发表时间：
2009-10-28
期刊：
影响因子：
--
通讯作者：
Pahan K
中科院分区：
文献类型：
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作者：
Ghosh A;Roy A;Matras J;Brahmachari S;Gendelman HE;Pahan K
帕金森病（PD）是仅次于阿尔茨海默病的最常见的破坏性人类神经退行性疾病。尽管进行了深入的研究，但目前尚无针对帕金森病的阻断性治疗方法。我们研究了辛伐他汀（一种fda批准的降胆固醇药物）是否可以预防模型PD小鼠1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）中毒后的黑质纹状体变性。首先，MPP+诱导小鼠小胶质细胞中p21ras和NF-κB的激活。p21ras的显性阴性突变Δp21ras抑制MPP+诱导的NF-κB的激活，支持p21ras参与MPP+诱导的NF-κB的小胶质活化。有趣的是，辛伐他汀在MPP+刺激的小胶质细胞中减弱了p21ras和NF-κB的活化。与此一致的是，我们发现mptp中毒小鼠体内黑质致密部中p21ras的激活非常快。然而，口服辛伐他汀后，辛伐他汀进入黑质，降低p21ras的神经活化，减弱NF-κB的神经活化，抑制促炎分子的神经表达，抑制神经胶质细胞的神经活化。这些发现与mptp中毒小鼠的多巴胺能神经元保护、纹状体神经递质正常化和运动功能改善相一致。同样，另一种降胆固醇药物普伐他汀抑制mptp中毒小鼠的小胶质细胞炎症反应并保护多巴胺能神经元；但浓度低于辛伐他汀。此外，发病2天后给予的两种他汀类药物仍然能够抑制多巴胺能神经元的死亡和伴随的神经递质损失，这表明他汀类药物能够减缓MPTP小鼠模型中神经元损失的进展。因此，我们得出结论，他汀类药物可能对PD患者有治疗益处。
Parkinson's disease (PD) is second only to Alzheimer's disease as the most common devastating human neurodegenerative disorder. Despite intense investigation, no interdictive therapy is available for PD. We investigated whether simvastatin, an FDA-approved cholesterol-lowering drug, could protect against nigrostriatal degeneration following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication to model PD in mice. First, MPP+ induced the activation of p21ras and NF-κB in mouse microglial cells. Inhibition of MPP+-induced activation of NF-κB by Δp21ras, a dominant-negative mutant of p21ras, supported the involvement of p21ras in MPP+-induced microglial activation of NF-κB. Interestingly, simvastatin attenuated activation of both p21ras and NF-κB in MPP+-stimulated microglial cells. Consistently, we found a very rapid activation of p21ras in vivo in the substantia nigra pars compacta of MPTP-intoxicated mice. However, after oral administration, simvastatin entered into the nigra, reduced nigral activation of p21ras, attenuated nigral activation of NF-κB, inhibited nigral expression of proinflammatory molecules, and suppressed nigral activation of glial cells. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. Similarly, pravastatin, another cholesterol-lowering drug, suppressed microglial inflammatory responses and protected dopaminergic neurons in MPTP-intoxicated mice; but at levels less than simvastatin. Furthermore, both the statins administered 2 days after initiation of the disease were still capable of inhibiting the demise of dopaminergic neurons and concomitant loss of neurotransmitters suggesting that statins are capable of slowing down the progression of neuronal loss in the MPTP mouse model. Therefore, we conclude that statins may be of therapeutic benefit for PD patients.