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Therapeutic Potential of Pioglitazone in a Propionic Acid-Induced Rat Model of Autism Spectrum Disorder: The Role of
Arife Erdoğan1, Mümin Alper Erdoğan2, Yiğit Uyanıkgil3
1Department of Emergency Medicine, Health Sciences University İzmir Tepecik Education and Research Hospital, Izmir, Türkiye.
Abstract:
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by social communication deficits and repetitive behaviours. Emerging evidence highlights neuroinflammation, oxidative stress and mitochondrial dysfunction in its pathogenesis. Propionic acid (PPA), an enteric short-chain fatty acid, is frequently utilized to replicate ASD-like phenotypes in rodents. This study investigated the therapeutic efficacy of pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist known for its neuroprotective and anti-inflammatory properties, in a PPA-induced rat model of ASD. Thirty male Wistar rats were randomly assigned to control, PPA + saline or PPA + pioglitazone (15 mg/kg/day, orally) groups. Neurobehavioural profiling utilized the sociability, open-field and passive avoidance learning tests. Furthermore, cerebral tissues were analysed for tumour necrosis factor-alpha (TNF-α), brain-derived neurotrophic factor (BDNF), sirtuin-1 (SIRT1), galectin-3 and malondialdehyde (MDA), alongside comprehensive histopathological evaluations of the hippocampus and cerebellum. Pioglitazone significantly improved social interaction, associative memory retention and spontaneous locomotor activity. Biochemically, the treatment significantly suppressed inflammatory and oxidative stress markers (TNF-α, galectin-3 and MDA) while increasing cerebral BDNF and SIRT1 levels. Histological assessments confirmed these neuroprotective benefits, demonstrating preserved neuronal architecture and decreased glial fibrillary acidic protein (GFAP) immunoreactivity, indicative of reduced reactive astrogliosis. These findings indicate that pioglitazone ameliorates behavioural, biochemical and histopathological alterations in the PPA-induced rat model of ASD. The concurrent restoration of cerebral SIRT1 levels suggests that SIRT1-related signalling may contribute to the observed neuroprotective effects.
