Alpha-lipoic acid attenuates valproic acid-induced autism-like phenotypes in zebrafish by enhancing antioxidant capacity and repressing oxidative stress, inflammation, apoptosis, and HPI-axis signaling.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with identified etiological mechanisms, yet effective treatments remain elusive. Individuals with ASD often exhibit compromised antioxidant defenses and are subject to oxidative stress. In this study, we used an established zebrafish (Danio rerio) model of autism with valproic acid (VPA) and subsequently administered 20 μg/mL Alpha-lipoic acid (ALA) to assess its effects on oxidative stress markers, transcriptional alterations in genes associated with autism, inflammatory mediators, apoptosis, the hypothalamic-pituitary-interrenal (HPI) axis, and aggressive behavior. Our results demonstrated that ALA treatment significantly enhanced the activity of antioxidant enzymes, particularly glutathione S-transferase (GST) and glutathione peroxidase (GPX), while increasing glutathione (GSH) levels and reducing malondialdehyde (MDA) concentrations. ALA treatment resulted in lower expression levels of inflammatory cytokines TNF-α and IL-6 mRNA. ALA downregulated the expression of apoptotic markers such as caspase-3, caspase-8, and caspase-9, as well as decrease the number of apoptotic cells. Additionally, behavioral assessments indicated a restoration of aggressive behavior, alongside a reduction in the expression of HPI axis-related hormones, including CRHα, CRHβ, UI, GR and MR, leading to decreased systemic cortisol level. Furthermore, ALA treatment reduced the expression of autism-related genes like shank3a, chd8, adsl, and mbd5. Molecular docking analyses suggest ALA may directly interact with proteins from these genes, offering new insights into its role in autism-related pathways. Collectively, our findings suggest that ALA may mitigate VPA-induced ASD-like symptoms by enhancing antioxidant capacity, alleviating oxidative stress, modulating inflammatory responses, and repressing apoptotic and HPI axis activity, thereby offering a potential therapeutic avenue for the management of ASD symptoms.