Ertugliflozin improves animal behaviours associated with oxidative stress and inflammation in a BTBR T + Itpr3tf/J mouse model of autism

  • Brain Commun. 2026 Mar 11;8(2):fcag083. doi: 10.1093/braincomms/fcag083.
Xiaona Wang  1 ,  Zhengqin Zhao  2 ,  Limin Sun  3 ,  Chao Gao  4 ,  Li Wang  5 ,  Daoqi Mei  6 ,  Chanjuan Hao  7 ,  Shuai Zhao  1 ,  Xingxue Yan  1 ,  Jing Liu  1 ,  Lei Liu  1 ,  Bin Guo  8 ,  Yaodong Zhang  1
Affiliations
  • 1. Henan Key Laboratory of Genetic and Developmental Disorders, Henan Children's Neurodevelopment Engineering Research Center, Henan Academy of Medical Sciences, Children's Hospital Affiliated to Zhengzhou University, Henan Children's Hospital, Institute of Children's Health, Zhengzhou 450018, China.
  • 2. Department of Nuclear Medicine, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China.
  • 3. Shanghai Institute of Microsystem and Information Technology, Shanghai, China.
  • 4. Department of Rehabilitation, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China.
  • 5. Department of Neurology, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, China.
  • 6. Department of Neurology, Children's Hospital Affiliated to Soochow University, Suzhou, China.
  • 7. Beijing Key Laboratory for Genetics of Birth Defects, Beijing Pediatric Research Institute, MOE Key Laboratory of Major Diseases in Children, Genetics and Birth Defects Control Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
  • 8. Physiology and Psychology Section, Ningxia Regional Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Regional High Incidence Disease, Ningxia Medical University, Yinchuan City 750004, China.
PMID: 41907315 DOI: 10.1093/braincomms/fcag083
Abstract

Autism spectrum disorder is a neurodevelopmental condition typified by difficulties in social interactions, repetitive and restricted behaviour and heightened anxiety. Increasing evidence suggests that oxidative stress and neuroinflammatory processes are crucial in the development of these behavioural 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 autism spectrum disorder, as they show core autism-like behavioural features. The present study investigated whether ertugliflozin could ameliorate autism spectrum disorder-like behaviour in BTBR mice and explored the associated mechanisms. It was found that ertugliflozin treatment significantly improved social interaction while reducing repetitive behaviours 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 autism spectrum disorder-like behavioural 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 autism spectrum disorder.

Keywords
autism spectrum disorder; ertugliflozin; inflammation; microglia; oxidative stress.
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