title: A PPAR-β/δ agonist is neuroprotective and decreases cognitive impairment in a rodent model of Parkinson's disease.
abstract: Parkinson's disease (PD) is associated with higher risk of cognitive impairment that may lead to memory loss, confusion, and decreased attention span. In this study, we have investigated the effect of GW0742, a PPAR-β/δ agonist in rat model of cognitive impairment associated with PD. Bilateral intranigral administration of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) (100 µg/1 µl/side) produced significant cognitive dysfunctions. PPAR-β/δ agonist GW0742 at a dose of 30 and 100 µg/kg showed significant improvement in cognitive impairments caused by MPTP in rat model of PD as evident from passive avoidance and Morris water maze test. MPTP-induced massive oxidative damage and DNA fragmentation was ameliorated by GW0742 treatment as observed after MDA and GSH estimation and TUNEL assay. Tyrosine hydroxylase positive neurons were decreased by 25% of normal control in MPTP group and GW0742 treatment restored tyrosine hydroxylase levels showing neuroprotective nature. Further, we performed physiologically based pharmacokinetic (PBPK) modeling study using GastroPlus to characterize the kinetics of GW0742 in the brain. The predicted amounts of GW0742 in brain suggest that it has the ability to cross the blood brain barrier. This study implicates the involvement of PPAR-β/δ in PD induced cognitive impairment.
authors.forename: Nihar R
authors.initials: NR
authors.lastname: Das
authors.forename: Rahul P
authors.initials: RP
authors.lastname: Gangwal
authors.forename: Mangesh V
authors.initials: MV
authors.lastname: Damre
authors.forename: Abhay T
authors.initials: AT
authors.lastname: Sangamwar
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, SAS Nagar, Punjab-160062, India. sssharma@niper.ac.in.
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Sharma
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D020287:In Situ Nick-End Labeling; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D047494:PPAR delta / Q000819:agonists; D048068:PPAR-beta / Q000819:agonists; D020734:Parkinsonian Disorders / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013844:Thiazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D010636:Phenols; D013438:Sulfhydryl Compounds
chemical_list: D018696:Neuroprotective Agents; D047494:PPAR delta; D048068:PPAR-beta; D013844:Thiazoles; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds