Ghosh Anamitra, Roy Avik, Matras Joanna, Brahmachari Saurav, Gendelman Howard E, Pahan Kalipada
Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, USA.
J Neurosci. 2009 Oct 28;29(43):13543-56. doi: 10.1523/JNEUROSCI.4144-09.2009.
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, a Food and Drug Administration-approved cholesterol-lowering drug, could protect against nigrostriatal degeneration after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication to model PD in mice. First, MPP(+) induced the activation of p21(ras) and nuclear factor-kappaB (NF-kappaB) in mouse microglial cells. Inhibition of MPP(+)-induced activation of NF-kappaB by Deltap21(ras), a dominant-negative mutant of p21(ras), supported the involvement of p21(ras) in MPP(+)-induced microglial activation of NF-kappaB. Interestingly, simvastatin attenuated activation of both p21(ras) and NF-kappaB in MPP(+)-stimulated microglial cells. Consistently, we found a very rapid activation of p21(ras) 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 p21(ras), attenuated nigral activation of NF-kappaB, 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 d 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.
帕金森病（PD）是仅次于阿尔茨海默病的最常见的严重人类神经退行性疾病。尽管进行了深入研究，但尚无针对PD的阻断性治疗方法。我们研究了一种经美国食品药品监督管理局批准的降胆固醇药物辛伐他汀，在1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）中毒以在小鼠中模拟PD后，是否能预防黑质纹状体变性。首先，MPP(+)诱导小鼠小胶质细胞中p21(ras)和核因子-κB（NF-κB）的激活。p21(ras)的显性负性突变体Deltap21(ras)对MPP(+)诱导的NF-κB激活的抑制作用，支持了p21(ras)参与MPP(+)诱导的小胶质细胞NF-κB激活。有趣的是，辛伐他汀减弱了MPP(+)刺激的小胶质细胞中p21(ras)和NF-κB的激活。一致地，我们发现MPTP中毒小鼠黑质致密部体内p21(ras)非常快速地激活。然而，口服给药后，辛伐他汀进入黑质，降低黑质p21(ras)的激活，减弱黑质NF-κB的激活，抑制促炎分子在黑质的表达，并抑制黑质胶质细胞的激活。这些发现与多巴胺能神经元保护、使MPTP中毒小鼠纹状体神经递质正常化以及改善运动功能相平行。同样，另一种降胆固醇药物普伐他汀在MPTP中毒小鼠中抑制小胶质细胞炎症反应并保护多巴胺能神经元，但程度低于辛伐他汀。此外，在疾病开始后2天给予这两种他汀类药物仍能够抑制多巴胺能神经元的死亡和伴随的神经递质丧失，表明他汀类药物能够减缓MPTP小鼠模型中神经元丧失的进程。因此，我们得出结论，他汀类药物可能对PD患者具有治疗益处。
