Title:A PPAR-β/δ Agonist is Neuroprotective and Decreases Cognitive Impairment in a Rodent Model of Parkinson’s Disease
Volume: 11
Issue: 2
Author(s): Nihar R. Das, Rahul P. Gangwal, Mangesh V. Damre, Abhay T. Sangamwar and Shyam S. Sharma
Affiliation:
Keywords:
GastroPlus, GW0742, MPTP, parkinson’s disease, PBPK modeling, PPAR beta.
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.
