Schintu Nicoletta, Frau Lucia, Ibba Marcello, Caboni Pierluigi, Garau Arianna, Carboni Ezio, Carta Anna R
Department of Toxicology, National Institute of Neuroscience, University of Cagliari, via Ospedale 72, 09124 Cagliari, Italy.
Eur J Neurosci. 2009 Mar;29(5):954-63. doi: 10.1111/j.1460-9568.2009.06657.x. Epub 2009 Feb 24.
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.
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-γ）具有选择性激动活性。PPAR-γ可调节大脑中的炎症反应，其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）诱导的进行性帕金森病（PD）小鼠模型，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。长期用MPTPp处理的小鼠表现出PD的典型特征，包括运动和嗅觉功能受损，伴有黑质致密部（SNc）中酪氨酸羟化酶（TH）阳性神经元部分丧失，尾状核-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，SNc和CPu中有强烈的小胶质细胞和星形胶质细胞反应。与MPTPp联合给药的慢性罗格列酮完全预防了运动和嗅觉功能障碍以及SNc中TH阳性细胞的丧失。在CPu中，纹状体DA的丧失得到部分预防，而DOPAC含量和Dyn的降低则被完全抵消。此外，通过CD11b免疫染色测量，罗格列酮完全抑制了SNc和CPu中小胶质细胞的反应性，并通过胶质纤维酸性蛋白免疫反应性评估部分抑制了星形胶质细胞反应。慢性治疗后2、4、6小时和3天纹状体MPP+水平的测量表明，罗格列酮未改变MPTP的代谢。这些结果支持将PPAR-γ激动剂作为一种旨在阻止PD进展的抗炎治疗方法，并建议在PD临床试验中进行评估。
