ROSIGLITAZONE DECREASES PEROXISOME PROLIFERATOR RECEPTOR-GAMMA LEVELS IN MICROGLIA AND INHIBITS TNF-ALPHA PRODUCTION: NEW EVIDENCES ON NEUROPROTECTION IN A PROGRESSIVE PARKINSON'S DISEASE MODEL
ROSIGLITAZONE DECREASES PEROXISOME PROLIFERATOR RECEPTOR-GAMMA LEVELS IN MICROGLIA AND INHIBITS TNF-ALPHA PRODUCTION: NEW EVIDENCES ON NEUROPROTECTION IN A PROGRESSIVE PARKINSON'S DISEASE MODEL
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DOI：
10.1016/j.neuroscience.2011.07.046
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发表时间：
2011-10-27
期刊：
影响因子：
3.3
通讯作者：
Carboni, E.
中科院分区：
文献类型：
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作者：
Carta, A. R.;Frau, L.;Carboni, E.
噻唑烷二酮(TZD)类过氧化物酶体增殖物受体γ(PPAR-γ)激动剂在实验性帕金森病(PD)模型中显示出神经保护作用。神经元和小胶质细胞表达PPAR-γ，因此它们都是神经保护的潜在靶点，尽管每种细胞类型的作用尚不清楚。此外，还涉及到受体依赖和受体非依赖的机制。本研究进一步探讨了TZD对帕金森病的神经保护作用机制。我们研究了罗格列酮在进行性MPTP/丙磺舒(MPTPp)帕金森病模型中的作用。C57BL/6J小鼠给予MPTP(25 mg/kg)+丙磺舒(100 mg/kg)，每周2次，连续5周。每天给予罗格列酮(10 mg/kg)，直到在MPTPP治疗的第四周开始，出现持续的神经变性和小胶质细胞增多症。用免疫荧光和共聚焦显微镜观察黑质致密部(SNC)酪氨酸羟化酶(TH)阳性神经元和CD11b阳性小胶质细胞中PPAR-γ水平的变化。慢性MPTPP处理诱导了TH阳性神经元和小胶质细胞中PPAR-γ的过度表达(分别为Vehicle的139.9%和121.7%)。给予MPTPP处理的小鼠，罗格列酮可逆转小胶质细胞中PPAR-y的过度表达，而不影响TH阳性神经元。随后观察小胶质细胞CD11b和肿瘤坏死因子-α(TNF-α)免疫反应性的变化。MPTPp逐渐增强CD11b的免疫反应性，使小胶质细胞具有高度活化的形态。此外，MPTPP后肿瘤坏死因子-α水平升高了457.38%。罗格列酮可拮抗MPTPp引起的CD11b免疫反应增强。此外，罗格列酮使肿瘤坏死因子-α的表达恢复到对照水平。黑质纹状体退行性变通过纹状体多巴胺含量的测定和黑质TH阳性神经元的计数来评估。MPTPP治疗可引起纹状体多巴胺的严重下降和黑质的部分变性。罗格列酮阻止了这两个区域的退化过程。结果提示，小胶质细胞PPAR-γ的表达及其产生的肿瘤坏死因子-α是罗格列酮对帕金森病起神经保护作用的重要机制。(C)2011年IBRO。爱思唯尔有限公司出版。保留所有权利。
Thiazolidinedione (TZD) class of peroxisome proliferator receptor gamma (PPAR-gamma) agonists display neuroprotective effects in experimental Parkinson's disease (PD) models. Neurons and microglia express PPAR-gamma, therefore both of them are potential targets for neuroprotection, although the role of each cell type is not clear. Moreover, receptor-dependent as well as receptor-independent mechanisms have been involved. This study further investigated mechanisms of TZD-mediated neuroprotection in PD. We investigated the rosiglitazone effect in the progressive MPTP/probenecid (MPTPp) model of PD. C57BL/6J mice received MPTP (25 mg/kg) plus probenecid (100 mg/kg) twice per week for 5 weeks. Rosiglitazone (10 mg/kg) was given daily until sacrifice, starting on the fourth week of MPTPp treatment, in presence of an ongoing neurodegeneration with microgliosis. Changes in PPAR-gamma levels were measured by immunofluorescence and confocal microscopy in tyrosine hydroxylase (TH)-positive neurons and CD11b-positive microglia of the substantia nigra pars compacta (SNc). Chronic MPTPp treatment induced a PPAR-gamma overexpression in both TH-positive neurons and microglia (139.9% and 121.7% over vehicle, respectively). Rosiglitazone administration to MPTPp-treated mice, reverted PPAR-y overexpression in microglia without affecting TH-positive neurons. Thereafter, changes in CD11b and tumor necrosis factor alpha (TNF-alpha) immunoreactivity in microglia were evaluated in the SNc. MPTPp progressively increased CD11b immunoreactivity, conferring to microglia a highly activated morphology. Moreover, TNF-alpha levels were increased (457.38% over vehicle) after MPTPp. Rosiglitazone administration counteracted the increase in CD11b immunoreactivity caused by MPTPp. Moreover, rosiglitazone reverted TNF-alpha expression to control levels. Nigrostriatal degeneration was assessed by high pressure liquid chromatography (HPLC) measurement of striatal dopamine, and counting of TH-positive neurons in the SNc. MPTPp treatment caused a severe decline of striatal dopamine and a partial degenera- tion of the SNc. Rosiglitazone arrested the degenerative process in both areas. Results suggest that PPAR-gamma expression in microglia and TNF-alpha production by these cells are crucial changes by which rosiglitazone exerts neuroprotection in PD. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.