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

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

Authors
Type
Published Article
Journal
Journal of Drug and Alcohol Research
Publisher
Ashdin Publishing
Volume
2
Pages
1–9
Identifiers
DOI: 10.4303/jdar/235611
Source
Ashdin
Keywords
License
Green

Abstract

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/IGF-1 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.

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