Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP model of Parkinson's disease.
Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP model of Parkinson's disease.
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DOI：
10.1186/1742-2094-9-38
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发表时间：
2012-02-22
影响因子：
9.3
通讯作者：
Labandeira-Garcia JL
中科院分区：
文献类型：
--
作者：
Garrido-Gil P;Joglar B;Rodriguez-Perez AI;Guerra MJ;Labandeira-Garcia JL
最近的几项研究表明，血管紧张素1型受体（AT 1）拮抗剂，如坎地沙坦抑制小胶质细胞炎症反应和多巴胺能细胞的损失在帕金森病的动物模型。然而，AT 1阻滞剂在脑中的神经保护和抗炎作用的机制尚未阐明。许多研究报告AT 1阻断剂激活过氧化物酶体增殖物激活受体γ（PPAR γ）。PPAR-γ激活抑制炎症，并可能负责神经保护作用，独立于AT 1阻断作用。我们研究了口服替米沙坦（AT 1阻断剂中最有效的PPAR-γ激活剂）是否可提供针对多巴胺能细胞死亡和神经炎症的神经保护，以及PPAR-γ激活在任何此类神经保护中的可能作用。我们使用多巴胺能神经毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导的帕金森病小鼠模型并同时给予PPAR-γ拮抗剂GW 9662来研究PPAR-γ激活的作用。此外，我们使用MPTP损伤的AT 1a缺失小鼠来研究在不存在任何AT 1阻断剂药理作用的情况下AT 1缺失是否提供神经保护，并研究通过共同施用PPAR-γ拮抗剂GW 9662是否也可能参与AT 1缺失的任何此类作用。我们观察到，替米沙坦保护小鼠多巴胺能神经元，抑制MPTP诱导的小胶质细胞反应。替米沙坦对多巴胺能细胞死亡和小胶质细胞活化的保护作用可被GW 9662联合给药抑制。多巴胺能细胞死亡和小胶质细胞活化显着降低AT 1a-null小鼠与MPTP治疗比在小鼠没有受到AT 1a删除。有趣的是，AT 1缺失的保护作用也被GW 9662的共同施用抑制。结果表明，替米沙坦对多巴胺能细胞死亡提供了有效的神经保护作用，并且神经保护作用是由PPAR-γ激活介导的。然而，在AT 1缺陷小鼠中的结果表明，AT 1的阻断，与AT 1阻断剂的药理学特性无关，也可以防止多巴胺能细胞死亡和神经炎症。此外，结果表明，PPAR-γ活化参与AT 1缺失的抗炎和神经保护作用。
Several recent studies have shown that angiotensin type 1 receptor (AT1) antagonists such as candesartan inhibit the microglial inflammatory response and dopaminergic cell loss in animal models of Parkinson's disease. However, the mechanisms involved in the neuroprotective and anti-inflammatory effects of AT1 blockers in the brain have not been clarified. A number of studies have reported that AT1 blockers activate peroxisome proliferator-activated receptor gamma (PPAR γ). PPAR-γ activation inhibits inflammation, and may be responsible for neuroprotective effects, independently of AT1 blocking actions. We have investigated whether oral treatment with telmisartan (the most potent PPAR-γ activator among AT1 blockers) provides neuroprotection against dopaminergic cell death and neuroinflammation, and the possible role of PPAR-γ activation in any such neuroprotection. We used a mouse model of parkinsonism induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and co-administration of the PPAR-γ antagonist GW9662 to study the role of PPAR-γ activation. In addition, we used AT1a-null mice lesioned with MPTP to study whether deletion of AT1 in the absence of any pharmacological effect of AT1 blockers provides neuroprotection, and investigated whether PPAR-γ activation may also be involved in any such effect of AT1 deletion by co-administration of the PPAR-γ antagonist GW9662. We observed that telmisartan protects mouse dopaminergic neurons and inhibits the microglial response induced by administration of MPTP. The protective effects of telmisartan on dopaminergic cell death and microglial activation were inhibited by co-administration of GW9662. Dopaminergic cell death and microglial activation were significantly lower in AT1a-null mice treated with MPTP than in mice not subjected to AT1a deletion. Interestingly, the protective effects of AT1 deletion were also inhibited by co-administration of GW9662. The results suggest that telmisartan provides effective neuroprotection against dopaminergic cell death and that the neuroprotective effect is mediated by PPAR-γ activation. However, the results in AT1-deficient mice show that blockage of AT1, unrelated to the pharmacological properties of AT1 blockers, also protects against dopaminergic cell death and neuroinflammation. Furthermore, the results show that PPAR-γ activation is involved in the anti-inflammatory and neuroprotective effects of AT1 deletion.
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影响因子：
15.1
作者：
Fuchtbauer, L.;Groth-Rasmussen, M.;Owens, T.
通讯作者：
Owens, T.
影响因子：
5
作者：
Ji, Yuanyuan;Liu, Juntian;Gou, Wei
通讯作者：
Gou, Wei
影响因子：
5.3
作者：
Combs, CK;Johnson, DE;Landreth, GE
通讯作者：
Landreth, GE
影响因子：
--
作者：
Basso, N;Paglia, N;Inserra, F
通讯作者：
Inserra, F
影响因子：
3.3
作者：
Carta, A. R.;Frau, L.;Carboni, E.
通讯作者：
Carboni, E.