Exploring the therapeutic potential of PPARα in schizophrenia

Abstract

Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor that regulates lipid metabolism and inflammatory responses. Recent studies have revealed that PPARα also plays an important role in maintaining neuronal homeostasis through modulation of fatty-acid oxidation and inflammation in the brain. Our previous work using both animal models and human samples has demonstrated that PPARα is involved in the pathophysiology of schizophrenia. Ppara-deficient mice exhibit reduced prepulse inhibition, increased anxiety-like behavior, and decreased dendritic spine density with a reduction of mature spines in the prefrontal cortex. In patients with schizophrenia, decreased expression of the PPARA gene in hair-follicle cells and loss-of-function variants of PPARA have been identified, suggesting that impairment of PPARα signaling contributes to disease development. Moreover, administration of a PPARα agonist ameliorates dendritic spine abnormalities and behavioral deficits in phencyclidine (PCP)-treated model mice. Other groups have reported that prenatal treatment with PPARα agonists improves adult behavioral abnormalities and suppresses fetal cytokine elevation in maternal immune-activation models. In addition, PPARα agonists have shown beneficial effects in animal models and clinical studies of autism spectrum disorder and depression. Collectively, these findings indicate that PPARα represents a novel therapeutic target that bridges metabolic, neurodevelopmental, and neurodegenerative mechanisms, offering new opportunities for drug discovery in psychiatric and neurological disorders.