PPAR-gamma-mediated neuroprotection in a chronic mouse model of Parkinson's disease
PPAR-gamma-mediated neuroprotection in a chronic mouse model of Parkinson's disease
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DOI：
10.1111/j.1460-9568.2009.06657.x
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发表时间：
2009-03-01
影响因子：
3.4
通讯作者：
Carta, Anna R.
中科院分区：
文献类型：
--
作者：
Schintu, Nicoletta;Frau, Lucia;Carta, Anna R.
罗格列酮是一种常用的胰岛素增敏药物，对过氧化物酶体增殖物激活受体-γ（PPAR-gamma）具有选择性激动活性。PPAR-gamma可以调节大脑中的炎症反应，激动剂可能对神经退行性疾病有益。在本研究中，我们使用慢性1-甲基-4-苯基-1，2，3，6-四氢吡啶加丙磺舒（MPTPp）小鼠模型进行性帕金森病（PD），以评估罗格列酮对行为障碍，神经退行性变和炎症的治疗效果。慢性MPTP处理的小鼠表现出典型的PD特征，包括运动和嗅觉功能受损，与黑质腹侧部（SNc）酪氨酸羟化酶（TH）阳性神经元的部分缺失相关，尾壳核（CPu）中多巴胺（DA）和3，4-二羟基苯乙酸（DOPAC）含量以及强啡肽（Dyn）mRNA水平降低，在SNc和CPu中强烈的小胶质细胞和星形胶质细胞反应。长期罗格列酮联合MPTP p给药可完全预防运动和嗅觉功能障碍以及SNc中TH阳性细胞的丢失。在CPu中，纹状体DA的损失被部分阻止，而DOPAC含量和Dyn的减少被完全抵消。此外，罗格列酮完全抑制SNc和CPu中的小胶质细胞反应，如通过CD 11b免疫染色测量的，并且部分抑制通过胶质细胞酸性蛋白免疫反应评估的星形胶质细胞反应。慢性治疗后2、4、6 h和3 d测量纹状体MPP+水平表明，罗格列酮未改变MPTP代谢。结果支持使用PPAR-gamma激动剂作为一种假定的抗炎治疗，旨在阻止PD进展，并建议在PD临床试验中进行评估是必要的。
Rosiglitazone is a commonly prescribed insulin-sensitizing drug with a selective agonistic activity on the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). PPAR-gamma can modulate inflammatory responses in the brain, and agonists might be beneficial in neurodegenerative diseases. In the present study we used a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine plus probenecid (MPTPp) mouse model of progressive Parkinson's disease (PD) to assess the therapeutic efficacy of rosiglitazone on behavioural impairment, neurodegeneration and inflammation. Mice chronically treated with MPTPp displayed typical features of PD, including impairment of motor and olfactory functions associated with partial loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc), decrease of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) content and dynorphin (Dyn) mRNA levels in the caudate-putamen (CPu), intense microglial and astroglial response in the SNc and CPu. Chronic rosiglitazone, administered in association with MPTPp, completely prevented motor and olfactory dysfunctions and loss of TH-positive cells in the SNc. In the CPu, loss of striatal DA was partially prevented, whereas decreases in DOPAC content and Dyn were fully counteracted. Moreover, rosiglitazone completely inhibited microglia reactivity in SNc and CPu, as measured by CD11b immunostaining, and partially inhibited astroglial response assessed by glial fibrillary acidic protein immunoreactivity. Measurement of striatal MPP+ levels 2, 4, 6 h and 3 days after chronic treatment indicated that MPTP metabolism was not altered by rosiglitazone. The results support the use of PPAR-gamma agonists as a putative anti-inflammatory therapy aimed at arresting PD progression, and suggest that assessment in PD clinical trials is warranted.