Abstract Autism spectrum disorder (ASD) is a neurodevelopmental condition typified by difficulties in social interactions, repetitive and restricted behavior, and heightened anxiety. Increasing evidence suggests that oxidative stress and neuroinflammatory processes are crucial in the development of these behavioral abnormalities. Ertugliflozin, a sodium-glucose cotransporter-2 inhibitor approved by the FDA for treating type 2 diabetes mellitus, has also been reported to exert antioxidant and anti-inflammatory effects. BTBR T+ Itpr3tf/J (BTBR) mice are widely used as a preclinical model of ASD, as they show core autism-like behavioral features. The present study investigated whether ertugliflozin could ameliorate ASD-like behavior in BTBR mice and explored the associated mechanisms. It was found that ertugliflozin treatment significantly improved social interaction while reducing repetitive behaviors and anxiety-like responses compared with untreated BTBR mice. Ertugliflozin (20 mg/kg/day), administered orally, reduced neuronal loss in the CA1 region of the hippocampus and the prefrontal cortex. In addition, ertugliflozin reduced oxidative stress, as demonstrated by decreased malondialdehyde levels, restoration of glutathione content, and improved activities of superoxide dismutase and catalase. A significant suppression of inflammatory cytokines accompanied these biochemical improvements. Furthermore, ertugliflozin significantly inhibited microglial activation in BTBR mice. Collectively, the findings indicate that ertugliflozin alleviates ASD-like behavioral deficits in BTBR mouse models, at least in part, by reducing oxidative stress and neuroinflammation. This study highlights ertugliflozin as a potential therapeutic candidate for the management of ASD.
Wang et al. (Tue,) studied this question.