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.

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