title: Neuroprotective efficacy of the peroxisome proliferator-activated receptor delta-selective agonists in vitro and in vivo.
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.
authors.affiliation: Neuroscience Discovery Research, Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. akinori.iwashita@jp.astellas.com
authors.forename: Akinori
authors.initials: A
authors.lastname: Iwashita
authors.forename: Yuko
authors.initials: Y
authors.lastname: Muramatsu
authors.forename: Takao
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Masakazu
authors.initials: M
authors.lastname: Muramoto
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kita
authors.forename: Shunji
authors.initials: S
authors.lastname: Yamazaki
authors.forename: Kayoko
authors.initials: K
authors.lastname: Mihara
authors.forename: Akira
authors.initials: A
authors.lastname: Moriguchi
authors.forename: Nobuya
authors.initials: N
authors.lastname: Matsuoka
mesh_terms: D000085:Acetates / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism / Q000517:prevention & control*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D047494:PPAR delta / Q000819:agonists* / Q000235:genetics; D010300:Parkinson Disease / Q000378:metabolism / Q000517:prevention & control*; D010636:Phenols / Q000493:pharmacokinetics / Q000494:pharmacology; D010642:Phenoxyacetates; D051381:Rats; D017208:Rats, Wistar; D013379:Substrate Specificity; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C520164:4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid; D000085:Acetates; C425931:GW 501516; D008024:Ligands; D018696:Neuroprotective Agents; D047494:PPAR delta; D010636:Phenols; D010642:Phenoxyacetates; D013844:Thiazoles; D020169:Caspases; D004298:Dopamine