PPAR Agonist Rescue of Ethanol-Impaired Brain Insulin Signaling: Cerebellar Slice Culture Model

Cerebellar abnormalities in fetal alcohol spectrum disorder (FASD) have been linked to brain insulin resistance and oxidative stress. Peroxisome proliferator-activated receptor (PPAR) agonists, which have insulin sensitizer and antioxidant effects, could potentially be used to treat neurodevelopmental abnormalities in FASD. Slice cultures generated with cerebella from control or ethanol-exposed rat pups were treated with vehicle, or a PPAR-α, PPAR-δ, or PPAR-γ agonist to examine effects on cytotoxicity, histopathology, insulin signaling, and neuronal/glial protein expression. PPAR agonists reduced ethanol-mediated cytotoxicity; restored cerebellar architecture; increased expression or activation of insulin/IGF1 receptors, IRS-1, Akt, and PRAS40; and inhibited GSK-3β. PPAR agonists increased the expression of Hu, myelin-associated glycoprotein-1, and choline acetyltransferase, and decreased the oxidative stress in ethanol-exposed cultures. The PPAR-δ and PPAR-γ agonists were more effective than the PPAR-α agonist in abrogating the adverse effects of ethanol. Therefore, early treatment with PPAR-δ or PPAR-γ agonists may help prevent long-term consequences of FASD.