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

Researchers gave pregnant rats a common anti-inflammatory medication (indomethacin) during pregnancy and studied the offspring as adults. The rat pups showed autism-like behaviors including reduced social interaction, less exploration, and motor difficulties - especially in males. Brain analysis revealed inflammation and chemical changes that may explain these behaviors. This suggests some medications during pregnancy might affect brain development.

This pre-clinical study examined whether prenatal exposure to indomethacin (a non-selective COX inhibitor) could induce autism-like changes in rat offspring. Pregnant rats received indomethacin during gestational days 10-14, and adult offspring were assessed for behavioral and neurobiological changes. Results showed reduced sociability, exploration, and motor performance, particularly in males. Biochemical analyses revealed decreased prostaglandin E and LC3B levels alongside increased oxidative stress markers.

Histological examination showed increased neuronal density in hippocampal CA1 region and elevated glial activation in hippocampus and cerebellum. The findings suggest prenatal prostaglandin synthesis inhibition may contribute to autism-relevant outcomes through oxidative stress, altered autophagy signaling, and neuroinflammatory processes.

Findings suggest caution regarding COX inhibitor use during critical prenatal windows, particularly given sex-specific effects. However, animal model limitations require careful interpretation. Research supports investigating prostaglandin signaling, autophagy, and oxidative stress pathways in autism etiology and potential therapeutic targets.

Animal model findings may not directly translate to humans. Study design details and sample sizes not fully specified in abstract. Long-term developmental outcomes beyond young adult age not assessed. Mechanism between prostaglandin inhibition and autism-like behaviors requires further validation.

Autism spectrum disorder (ASD) arises from interactions between genetic predisposition and prenatal environmental insults. Prostaglandin E(PGE), 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 PGE, 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 PGEand 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 PGEsignaling, leading to oxidative stress, altered autophagy-related signaling, and glial activation, which together contribute to ASD-relevant behavioral outcomes.