PX-478 Alleviated the Autism Spectrum Disorder Progression of Offspring Rats Induced by Prenatal Hypoxia

Background: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction, communication, repetitive behaviors, and narrow interests. This study aimed to investigate the impact of the Hypoxia-inducible factor-1 alpha (HIF-1α) inhibitor (PX-478) on ASD-like behaviors in rat offspring exposed to prenatal hypoxia (PH). Methods: Pregnant rats were randomly assigned to control or PH groups, with the latter experiencing six hours of hypoxia on the 17th day of gestation. Offspring were further treated with PX-478 treatment initiated at one week (+1 w) or three weeks (+3 w) after birth. Hippocampal histology was assessed using hematoxylin and eosin (HE) staining, while protein levels of HIF-1α and phosphatase and tensin homolog (PTEN) were analyzed via western blotting. The concentration of vascular endothelial growth factor (VEGF) was measured using an Enzyme-Linked Immunosorbent Assay (ELISA) kit. Results: PX-478 treatment significantly improved spatial memory, learning, and social ability, while reducing anxiety-like behavior in PH-exposed offspring rats. HE staining revealed that PX-478 treatment decreased the number of hippocampal neurons necrosis in offspring. However, PX-478 treatment at one week post-birth led to decreased body weight and elevated levels of alkaline phosphatase (ALP) and Alanine aminotransferase (ALT) in offspring rats, whereas no significant effect was observed after three weeks of treatment. Additionally, PX-478 treatment resulted in reduced HIF-1α protein levels in the hippocampus and VEGF concentration in the serum of PH-exposed offspring rats, along with elevated PTEN protein levels. Conclusions: The findings suggest that PX-478 treatment attenuated autism-like behavior in offspring. HIF-1α might play an important role in autism-like behavior induced by prenatal hypoxia, which may be realized by inhibiting PTEN activity.