Combination of Peroxisome Proliferator-activated Receptor Gamma (PPAR gamma) Agonist and PPAR Gamma Co-Activator 1 alpha (PGC-1 alpha) Activator Ameliorates Cognitive Deficits, Oxidative Stress, and Inflammation in Rodent Model of Parkinson's Disease

Background: PPAR gamma co-activator 1 alpha (PGC-1 alpha) is known as the master regulator of mitochondria! biogenesis. It is also a co-activator of peroxisome proliferator-activated receptor-gamma (PPAR gamma) and plays a role in preventing mitochondrial dysfunction in several neurodegenerative disorders, including Parkinson's disease (PD). Depletion in the levels of these proteins has been linked to oxidative stress, inflammation, and DNA damage, all of which are known to contribute to the pathogenesis of PD. Objective: In the present study, combination therapy of PPAR gamma agonist (GW1929) and PGC-1 alpha activator (alpha-lipoic acid) was employed to ameliorate cognitive deficits, oxidative stress, and inflammation associated with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. Methods: PD was induced using a bilateral intranigral administration of MPTP in Sprague Dawley rats, and different parameters were evaluated. Results: Our study showed that MPTP-induced PD rats exhibited an increase in oxidative stress and inflammation, leading to cognitive deficits. Furthermore, MPTP-induced PD rats also exhibited reduced mitochondria! biogenesis in comparison to control and sham animals. Intraperitoneal administration of GW 1929 and alpha-lipoic acid in doses lower than those earlier reported individually in literature led to an improvement in the cognitive deficits in comparison to MPTP-induced PD rats. These improvements were accompanied by a reduction in the levels of oxidative stress and inflammation. In addition, an increase in mitochondrial biogenesis was also observed after the combination of these pharmacological agents. Conclusion: Our results provide a rationale for the development of agents targeting PPAR gamma and PGC-1 alpha as potent therapeutics for the treatment of neurological diseases like PD.