Neuroprotective efficacy of the peroxisome proliferator-activated receptor δ-selective Agonists in vitro and in vivo
Neuroprotective efficacy of the peroxisome proliferator-activated receptor δ-selective Agonists in vitro and in vivo
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DOI：
10.1124/jpet.106.115758
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发表时间：
2007-03-01
影响因子：
3.5
通讯作者：
Matsuoka, Nobuya
中科院分区：
文献类型：
--
作者：
Iwashita, Akinori;Muramatsu, Yuko;Matsuoka, Nobuya
过氧化物酶体增殖物激活受体（PPARs）是核受体超家族的成员，作为配体调节的转录因子发挥作用，在许多重要的生物学过程中调节基因表达。PPARδ亚型在大脑中表达最高，据推测在神经元细胞功能中起主要作用；然而，该受体的确切生理作用仍有待阐明。在此，我们表明高亲和力的PPARδ激动剂L - 165041[4 - [3 - (4 - 乙酰基 - 3 - 羟基 - 2 - 丙基苯氧基)丙氧基]苯氧基] - 乙酸]和GW501516[2 - 甲基 - 4 - ((4 - 甲基 - 2 - (4 - 三氟甲基苯基) - 1,3 - 三唑 - 5 - 基)甲硫基)苯氧基乙酸]在体外可防止细胞毒素诱导的SH - SY5Y细胞损伤，在体内可防止缺血性脑损伤和1 - 甲基 - 4 - 苯基 - 1,2,3,6 - 四氢吡啶（MPTP）神经毒性。在SH - SY5Y研究中，用L - 165041或GW501516处理显著且浓度依赖性地减轻了毒胡萝卜素、1 - 甲基 - 4 - 苯基吡啶鎓或星形孢菌素暴露后的细胞死亡，损伤程度与半胱天冬酶 - 3抑制水平相关。在大鼠短暂性（90分钟）大脑中动脉闭塞缺血性脑损伤模型中，脑室内输注L - 165041或GW501516显著减轻了再灌注24小时后测量的缺血性脑损伤。此外，PPARδ激动剂还显著减轻了MPTP诱导的小鼠脑内纹状体多巴胺及相关代谢物含量的减少。这些结果表明，亚型选择性的PPARδ激动剂在体外具有抗凋亡特性，这可能是它们在脑缺血和帕金森病（PD）体内实验模型中潜在神经保护作用的基础。这些发现提示PPARδ激动剂可能是了解PPARδ在其他神经退行性疾病中作用的有用工具，也是中风和帕金森病等神经退行性疾病有吸引力的治疗候选药物。
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily and function as ligand-modulated transcription factors that regulate gene expression in many important biological processes. The PPAR delta subtype has the highest expression in the brain and is postulated to play a major role in neuronal cell function; however, the precise physiological roles of this receptor remain to be elucidated. Herein, we show that the high-affinity PPAR delta agonists L-165041 [4-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxyl]phenoxy]-acetic acid] and GW501516 [2-methyl4-((4-methyl-2-(4-trifluoromethylphenyl)-1,3-triazol-5-yl)methylsulfanyl) phenoxy acetic acid] protect against cytotoxin-induced SH-SY5Y cell injury in vitro and both ischemic brain injury and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in vivo. In the SH-SY5Y studies, treatment with L-165041 or GW501516 significantly and concentration-dependently attenuated cell death following thapsigargin, 1-methyl-4-phenylpyridinium, or staurosporine exposure, with the extent of damage correlated with the level of caspase-3 inhibition. In the transient (90 min) middle cerebral artery occlusion model of ischemic brain injury in rats, i.c.v. infusion of L-165041 or GW501516 significantly attenuated the ischemic brain damage measured 24 h after reperfusion. Moreover, the PPAR delta agonists also significantly attenuated MPTP-induced depletion of striatal dopamine and related metabolite contents in mouse brain. These results demonstrate that subtype-selective PPAR delta agonists possess antiapoptotic properties in vitro, which may underlie their potential neuroprotective potential in in vivo experimental models of cerebral ischemia and Parkinson's disease (PD). These findings suggest that PPAR delta agonists could be useful tools for understanding the role of PPAR delta in other neurodegenerative disorders, as well as attractive therapeutic candidates for stroke and neurodegenerative diseases such as PD.