Diosgenin Ameliorates Behavioral Alterations, Hippocampal Oxidative Stress Markers, and Apoptotic Deficits in a Rat Model of Autism Induced by Valproic Acid Publisher Pubmed



Dehkhodaei S ; Naghdibadi M R ; Ahadi R ; Azizi Y ; Dadseresht A ; Soleimani M ; Hajisoltani R
Source: Metabolic Brain Disease Published:2026

Abstract

Background and aim: Autism Spectrum Disorder (ASD) is characterized by difficulties in social communication, anxiety, and repetitive behaviors, and it may also be associated with cognitive memory impairment. The etiology of ASD is complex, and current treatments have limited efficacy in addressing all ASD-related symptoms. Diosgenin (Dios) has shown neuroprotective effects in various neurological conditions. This study aimed to investigate the effects of Dios on hippocampal oxidative stress, apoptosis, and behavioral outcomes in a Valproic acid (VPA) induced rat model of Autism. Methods: We examined the potential role of Dios in altering recognition memory behaviors in male rats prenatally exposed toVPA (600 mg/kg). The offspring received Dios (40 mg/kg) or Carboxymethyl cellulose (5 mg/kg) from postnatal day (PND) 23 to PND 52. Subsequently, these animals were tested with behavioral tests, including the Three-Chamber, Marble Burying, Open Field, and Passive Avoidance tests (n=8). Additionally, reactive oxygen species (ROS) markers (GSH, CAT, ROS, n=3), apoptotic markers (Caspase3, Bax, Bcl-2, n=3), and histological evaluations (Nissl staining) were performed. Results: VPA-exposed rats displayed Autism-like behavioral impairments, including deficits in recognition memory and increased repetitive/anxiety-like behaviors. Additionally, Caspase-3 and Bax were upregulated, and Bcl2 was downregulated in hippocampal tissues. The rats in the study displayed a reduced antioxidant function, as shown by the decreased levels of GSH and CAT. Treatment with Dios mitigated markers of apoptosis and ROS, and enhanced recognition memory behavior in rats exposed to VPA. Furthermore, those treated with Dios exhibited a decrease in dark cell rates in the CA1 region of the hippocampus. Conclusion: This study demonstrated that markers of apoptosis and oxidative stress are elevated in rats exposed to VPA. The administration of Dios significantly reduces these markers, which in turn alleviates neuronal damage in the hippocampus and behavioral symptoms. Overall, these findings provide preclinical evidence supporting the potential neuroprotective role of Dios in an experimental model of ASD. © The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2026.