Pharmacological manipulation of peroxisome proliferator-activated receptor γ (PPARγ) reveals a role for anti-oxidant protection in a model of Parkinson's disease.
Pharmacological manipulation of peroxisome proliferator-activated receptor γ (PPARγ) reveals a role for anti-oxidant protection in a model of Parkinson's disease.
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DOI：
10.1016/j.expneurol.2012.02.017
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发表时间：
2012-06
影响因子：
5.3
通讯作者：
Teismann, Peter
中科院分区：
文献类型：
--
作者：
Martin, Heather L.;Mounsey, Ross B.;Mustafa, Sarah;Sathe, Kinnari;Teismann, Peter
过氧化物酶体增殖物激活受体γ（PPARγ）激动剂已被证明在许多神经退行性疾病（包括帕金森病和阿尔茨海默病）中提供神经保护。这些保护作用主要被认为是由PPARγ的抗炎作用引起的，然而，越来越多的证据表明抗氧化机制也可能起作用。本研究探讨了PPARγ激动剂罗格列酮和PPARγ拮抗剂GW 9662对MPP+/MPTP（1-甲基-4-苯基吡啶/1-甲基-4-苯基-1，2，3，6-四氢吡啶）帕金森病模型的影响，重点关注氧化应激机制。罗格列酮减弱MPP+诱导的SH-SY 5 Y细胞活性氧的形成，同时上调谷胱甘肽-S-转移酶活性，但不上调超氧化物歧化酶活性。与GW 9662共处理未减弱这些反应，表明不需要激活PPARγ。通过免疫组织化学确定了体内黑质多巴胺能神经元（SNpc）的PPARγ定位，发现MPTP处理后7天，PPARγ水平上调。通过用GW 9662处理C57 BL 6小鼠证实了PPARγ在保护免受MPTP毒性中的重要性。用GW 9662处理增加了MPTP诱导的SNpc中的神经元损失，同时不影响MPTP诱导的纹状体多巴胺和3，4-二羟基苯乙酸的减少。GW 9662还引起盐水处理的小鼠的SNpc中的神经元损失。本文提供的证据支持抗氧化机制在PPARγ激动剂对神经退行性疾病的保护作用中的作用，但表明这些作用可能不依赖于PPARγ激活。它还证明了PPARγ活性对SNpc内神经元存活的重要性。我们研究了PPARγ在帕金森病模型中的作用。罗格列酮具有非PPARγ依赖性抗氧化作用。罗格列酮涉及谷胱甘肽-S-转移酶活性的上调。在神经毒素MPTP之后，PPARγ被上调。α-PPARγ拮抗作用对SNpc中的神经元具有毒性。
Peroxisome proliferator-activated receptor γ (PPARγ) agonists have been shown to provide neuroprotection in a number of neurodegenerative diseases including Parkinson's disease and Alzheimer's disease. These protective effects are primarily considered to result from the anti-inflammatory actions of PPARγ, however, there is increasing evidence that anti-oxidant mechanisms may also contribute. This study explored the impact of the PPARγ agonist rosiglitazone and the PPARγ antagonist GW9662 in the MPP+/MPTP (1-methyl-4-phenylpyridinium/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model of Parkinson's disease, focussing on oxidative stress mechanisms. Rosiglitazone attenuated reactive oxygen species formation induced by MPP+ in SH-SY5Y cells concurrent with an upregulation of glutathione-S-transferase activity, but not superoxide dismutase activity. These responses were not attenuated by cotreatment with GW9662 suggesting that PPARγ activation is not required. The localisation of PPARγ in vivo to dopaminergic neurons of the substantia nigra pars compacta (SNpc) was established by immunohistochemistry and PPARγ levels were found to be upregulated 7 days after MPTP treatment. The importance of PPARγ in protecting against MPTP toxicity was confirmed by treating C57BL6 mice with GW9662. Treatment with GW9662 increased MPTP-induced neuronal loss in the SNpc whilst not affecting MPTP-induced reductions in striatal dopamine and 3,4-dihdroxyphenylacetic acid. GW9662 also caused neuronal loss in the SNpc of saline-treated mice. The evidence presented here supports the role of anti-oxidant mechanisms in the protective effects of PPARγ agonists in neurodegenerative diseases, but indicates that these effects may be independent of PPARγ activation. It also demonstrates the importance of PPARγ activity for neuronal survival within the SNpc. ► We investigate the role of PPARγ in a model of Parkinson's disease. ► Rosiglitazone has PPARγ independent anti-oxidant effects. ► Rosiglitazone involves upregulation of glutathione-S-transferase activity. ► PPARγ is upregulated after the neurotoxin MPTP. ► PPARγ antagonism is toxic to neurons in the SNpc.
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