PPAR-? Agonist Rescue of Brain Insulin/IGF Signaling Impairments Following Developmental Exposure to Alcohol
Author(s): Alexandra Ewenczyk, Ashley Conoway, Jason Ziplow, Tran Le, Quynh-Giao Nguyen, William Cy Chen, Ming Tong, Valerie Zabala, and Suzanne M de la Monte
Background. Neurodevelopmental abnormalities in fetal alcohol spectrum disorder (FASD) are associated with impaired insulin and IGF signaling, which is needed for neuronal growth, survival, and plasticity. We characterized effects of the L-165,041 PPAR-δ agonist insulin sensitizer on cerebellar structure and function in relation to insulin/IGF and neurotrophin signaling in an FASD model. Methods. On postnatal days (P) 2, 4, 6, and 8, rat pups were administered (i.p.) 2 g/kg of ethanol or saline; and on P5, P7, P9, and P11, they were treated with saline or L-165,041. Rotarod tests assessed motor function. Cerebella were studied biochemically. Results. Ethanol-impaired motor function and signaling through the insulin receptor and Akt were abrogated by PPAR-δ agonist treatments, whereas neurotrophin expression was unaffected. Conclusions: PPAR-δ agonists may help normalize cerebellar function in FASD by supporting insulin signaling through cell survival pathways, but additional approaches are needed to restore neurotrophin expression for neuronal plasticity.