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Prenatal Indomethacin Exposure Is Associated With Autism-Relevant Behavioral Alterations Linked to Oxidative Stress
Bakiye Akbaş1, Ahmet Akbaş2, Nadir Adnan Hacım3
1Department of Obstetrics and Gynecology, Medical Faculty, Karadeniz Technical University, Trabzon, Turkey.
Insights
Prenatal exposure to indomethacin, a COX inhibitor, may induce autism-like behaviors in rats by disrupting prostaglandin E2 signaling, causing oxidative stress and neuroinflammation. These effects were more pronounced in male offspring.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Autism spectrum disorder (ASD) pathogenesis involves genetic and environmental factors.
- Prostaglandin E2 (PGE2), regulated by COX-2, is crucial for neurodevelopment and glia-neuron communication.
- Inhibiting PGE2 during gestation may negatively impact fetal brain development.
Purpose of the Study:
- To investigate if prenatal indomethacin exposure induces autism-like behaviors in rats.
- To explore potential sex differences in these induced alterations.
- To examine the underlying molecular and histological changes in the offspring's brains.
Main Methods:
- Pregnant Wistar rats received indomethacin (1 mg/kg) on gestational days 10-14.
- Offspring underwent behavioral assessments (sociability, exploration, motor function) at P50-P54.
- Hippocampal and cerebellar tissues were analyzed for PGE2, LC3B, MDA, neuronal density, and GFAP expression.
Main Results:
- Indomethacin exposure reduced sociability, exploration, and motor performance, particularly in males.
- Biochemical analysis revealed decreased PGE2 and LC3B, and increased MDA.
- Histological examination showed increased CA1 neuronal counts and elevated GFAP immunoreactivity in hippocampus and cerebellum, indicating astroglial activation and neuroinflammation.
Conclusions:
- Prenatal prostaglandin synthesis inhibition by indomethacin may lead to ASD-relevant behavioral outcomes.
- Mechanisms include disturbed PGE2 signaling, oxidative stress, altered autophagy, and glial activation.
- These findings highlight potential risks of COX inhibitors during pregnancy for neurodevelopment.
Abstract:
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.
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