Advances in PPARs Molecular Dynamics and Glitazones as a Repurposing Therapeutic Strategy through Mitochondrial Redox Dynamics against Neurodegeneration

Abstract

: Peroxisome proliferator activated receptors (PPARs) activity exhibit significant implications for the development of novel therapeutic modalities against neurodegenerative diseases. PPAR-α, PPAR-β/δ, and PPAR-γ nuclear receptors expression are significantly reported in the brain, their implications in brain physiology and other neurodegenerative diseases still require extensive studies. PPAR signaling can modulate various cell signaling mechanisms involved inside the cells contributing to on- and -off target actions selectively to promote therapeutic effects as well as the adverse effects of PPAR ligands. Both natural and synthetic ligands for the PPARα, PPARγ, and PPARβ/δ have been reported. PPARα (WY 14.643) and PPARγ agonists can confer neuroprotection by modulating mitochondrial dynamics through the redox system. The pharmacological effect of these agonists may deliver effective clinical responses by protecting vulnerable neurons to Aβ toxicity in Alzheimer’s disease (AD) patients. Therefore, the current review delineated the ligands interaction with 3D- PPARs to modulate neuroprotection and also deciphered the efficacy of numerous drugs viz., Aβ aggregation inhibitors, vaccines, and γ-secretase inhibitors against AD; this review elucidated the role of PPAR and their receptor isoforms in neural systems, and neurodegeneration in human beings. Further, we have substantially discussed the efficacy of PPREs as potent transcription factors in the brain, and the role of PPAR agonists in neurotransmission, PPAR gamma coactivator-1α (PGC-1α), and mitochondrial dynamics in neuroprotection during AD conditions. This review concludes with the statement; development of novel PPARs agonists may benefit patients with neurodegeneration mainly in AD patients to mitigate the pathophysiology & dementia subsequently to improve overall patient’s quality of life.