Prenatal Indomethacin Exposure Is Associated With Autism-Relevant Behavioral Alterations Linked to Oxidative Stress and Altered Autophagy-Related Signaling.

Autism spectrum disorder (ASD) arises from interactions between genetic predisposition and prenatal environmental insults. Prostaglandin E2 (PGE2), derived from cyclooxygenase-2 (COX-2), regulates neuronal differentiation and glia-neuron signaling; thus, its inhibition during gestation may impair neurodevelopment. To examine whether prenatal exposure to indomethacin, a non-selective COX inhibitor, induces autism-like alterations in rats with possible sex differences. Sixteen pregnant Wistar rats received indomethacin (1 mg/kg, gavage) on Gestational Days 10-14. Adult offspring (P50-P54) underwent behavioral tests (open-field, rearing, rotarod, and three-chamber sociability). Hippocampal and cerebellar tissues were analyzed for PGE2, LC3B (ELISA), MDA (TBARS), neuronal density, and GFAP expression (CA1, CA3 - Nissl, GFAP staining). Indomethacin reduced sociability, exploration, and motor performance, especially in males, and decreased PGE2 and LC3B while increasing MDA (p < 0.001). Histologically, CA1 neuronal counts increased while GFAP immunoreactivity was markedly elevated in hippocampal (CA1 and CA3) and cerebellar regions (p < 0.05), reflecting astroglial activation and neuroinflammatory remodeling. Prenatal inhibition of prostaglandin synthesis may disturb PGE2 signaling, leading to oxidative stress, altered autophagy-related signaling, and glial activation, which together contribute to ASD-relevant behavioral outcomes.