論文 - 詳細
| RRC ID | 42841 |
|---|---|
| 著者 | Iwashita A, Muramatsu Y, Yamazaki T, Muramoto M, Kita Y, Yamazaki S, Mihara K, Moriguchi A, Matsuoka N. |
| タイトル | Neuroprotective efficacy of the peroxisome proliferator-activated receptor delta-selective agonists in vitro and in vivo. |
| ジャーナル | J Pharmacol Exp Ther |
| Abstract |
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 PPARdelta 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 PPARdelta 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 PPARdelta agonists also significantly attenuated MPTP-induced depletion of striatal dopamine and related metabolite contents in mouse brain. These results demonstrate that subtype-selective PPARdelta 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 PPARdelta agonists could be useful tools for understanding the role of PPARdelta in other neurodegenerative disorders, as well as attractive therapeutic candidates for stroke and neurodegenerative diseases such as PD. |
| 巻・号 | 320(3) |
| ページ | 1087-96 |
| 公開日 | 2007-3-1 |
| DOI | 10.1124/jpet.106.115758 |
| PII | jpet.106.115758 |
| PMID | 17167170 |
| MeSH | Acetates / pharmacokinetics Acetates / pharmacology Animals Brain / drug effects* Brain / metabolism Brain Ischemia / metabolism Brain Ischemia / prevention & control* Caspases / metabolism Cell Line, Tumor Cell Survival / drug effects Disease Models, Animal Dopamine / metabolism Genes, Reporter Humans Ligands Male Mice Mice, Inbred C57BL Neuroprotective Agents / pharmacokinetics Neuroprotective Agents / pharmacology* PPAR delta / agonists* PPAR delta / genetics Parkinson Disease / metabolism Parkinson Disease / prevention & control* Phenols / pharmacokinetics Phenols / pharmacology Phenoxyacetates Rats Rats, Wistar Substrate Specificity Thiazoles / pharmacokinetics Thiazoles / pharmacology |
| IF | 3.561 |
| 引用数 | 104 |
| WOS 分野 | PHARMACOLOGY & PHARMACY |
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オルトメトリクス指標項目
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| 最多言及媒体 | Wikipedia |
| 各媒体での言及数の合計 | 3 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | CV-1(RCB0160) |