VALPROİK ASİTLE İNDÜKLENEN SIÇAN OTİZM SPEKTRUM BOZUKLUĞU MODELİNDE DİMETİL FUMARAT UYGULAMASININ OLASI TERAPÖTİK ETKİLERİNİN ARAŞTIRILMASI

Abstract

ABSTRACT Karadağ K., Investigation of the Possible Therapeutic Effects of Dimethyl Fumarate Administration in the Valproic Acid-Induced Rat Autism Spectrum Disorder Model, Hacettepe University Faculty of Medicine, Department of Medical Pharmacology, Ankara, 2024. Autism spectrum disorder (ASD); is a complex neurodevelopmental disorder characterized by social interaction deficit, limited interests, repetitive behaviors and sensory abnormalities. The etiopathogenesis of ASD is not fully known and there is no effective medical treatment for the core symptoms of ASD. In studies conducted in individuals with ASD and experimental ASD models, evidence on the role of oxidative stress and neuroinflammation in the etiopathogenesis of ASD are increasing. There are results that the activity of the Nrf2 (Nuclear erythroid-related 2 factor 2) pathway, which has a regulatory effect on the inflammatory response and cytoprotective to oxidative stress, is reduced in ASD. Dimethyl fumarate (DMF) is an clinically used Nrf2 activator with antioxidant and immunomodulatory effects used in the treatment of multiple sclerosis and psoriasis, although its mechanism of action is not fully known. In our study, we aimed to investigate the therapeutic effects of DMF on ASD symptoms in the ASD model induced by prenatal exposure to valproic acid (VPA) in rats. In the VPA-induced ASD model; physical development, sensorimotor development and social attachment were evaluated in the infancy period. DMF administration with oral gavage was started in the adolescence period. Therapeutic effects of DMF; were examined at behavioral and molecular levels by behavioral experiments evaluating repetitive behaviors, social interaction, compulsive-like behaviors, anxiety and locomotor activity. By using colorimetric tests and ELISA method oxidative stress and neuroinflammation-related markers were evaluated in cerebellum and prefrontal cortex (PFC). Prenatal VPA exposure impaired social attachment in both sexes and caused impairment in sensorimotor skills in female offspring. While dimethyl fumarate did not alter neuroinflammatory markers in the cerebellum and PFC in the ASD model, it augmented the decreased antioxidant response and rescued the social interaction deficit. Keywords: Autism, valproic acid, dimethyl fumarate, oxidative stress, neuroinflammation. Our study was supported by Hacettepe University Scientific Research Projects Coordination Unit with the project code THD-2022-19851.