Development of PPARγ Agonists for the Treatment of Neuroinflammatory and Neurodegenerative Diseases: Leriglitazone as a Promising Candidate

Increasing evidence suggests that the peroxisome proliferator-activated receptor gamma (PPAR gamma), a member of the nuclear receptor superfamily, plays an important role in physiological processes in the central nervous system (CNS) and is involved in cellular metabolism and repair. Cellular damage caused by acute brain injury and long-term neurodegenerative disorders is associated with alterations of these metabolic processes leading to mitochondrial dysfunction, oxidative stress, and neuroinflammation. PPAR gamma agonists have demonstrated the potential to be effective treatments for CNS diseases in preclinical models, but to date, most drugs have failed to show efficacy in clinical trials of neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease. The most likely explanation for this lack of efficacy is the insufficient brain exposure of these PPAR gamma agonists. Leriglitazone is a novel, blood-brain barrier (BBB)-penetrant PPAR gamma agonist that is being developed to treat CNS diseases. Here, we review the main roles of PPAR gamma in physiology and pathophysiology in the CNS, describe the mechanism of action of PPAR gamma agonists, and discuss the evidence supporting the use of leriglitazone to treat CNS diseases.

Automated summary

Increasing evidence suggests that PPAR gamma plays an important role in CNS physiology and is involved in cellular metabolism and repair. However, most PPAR gamma agonists have failed to show efficacy in clinical trials of neurodegenerative diseases, possibly due to insufficient brain exposure. Leriglitazone, a BBB-penetrant PPAR gamma agonist, is being developed as a potential treatment for CNS diseases. This review discusses the main roles of PPAR gamma, mechanism of action of PPAR gamma agonists, and the evidence supporting the use of leriglitazone.