A PPAR-β/δ Agonist is Neuroprotective and Decreases Cognitive Impairment in a Rodent Model of Parkinson's Disease

被引：44
作者：
Das, Nihar R. [1 ]
Gangwal, Rahul P. [2 ]
Damre, Mangesh V. [2 ]
Sangamwar, Abhay T. [2 ]
Sharma, Shyam S. [1 ]
机构：
[1] NIPER, Dept Pharmacol & Toxicol, Mol Neuropharmacol Lab, Sas Nagar 160062, Punjab, India
[2] NIPER, Dept Pharmacoinformat, Sas Nagar 160062, Punjab, India
来源：
CURRENT NEUROVASCULAR RESEARCH | 2014年 / 11卷 / 02期
关键词：
GastroPlus; GW0742; MPTP; parkinson's disease; PBPK modeling; PPAR beta; FOCAL CEREBRAL-ISCHEMIA; MORRIS WATER MAZE; TYROSINE-HYDROXYLASE; SUBSTANTIA-NIGRA; INTRACEREBROVENTRICULAR STREPTOZOTOCIN; MEMORY IMPAIRMENT; GAMMA AGONISTS; MOUSE MODEL; MPTP MODEL; IN-VITRO;
D O I：
10.2174/1567202611666140318114037
中图分类号：
R74 [神经病学与精神病学];
学科分类号：
摘要：
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-beta/delta 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 mu g/l mu l/side) produced significant cognitive dysfunctions. PPAR-beta/delta agonist GW0742 at a dose of 30 and 100 mu g/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-beta/delta in PD induced cognitive impairment.
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页码：114 / 124
页数：11
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