Hongmei Wu1, Yue Luan2, Hongzhi Wang3, Pengfei Zhang4, Sijin Liu5, Peng Wang6, Yonggang Cao7, Hongli Sun8, Lijie Wu9. 1. Department of Psychology, College of Nursing, Harbin Medical University in Daqing, Daqing, Heilongjiang 163319, China. Electronic address: woom@163.com. 2. Department of Child psychiatry, Daqing Third Hospital, Daqing, Heilongjiang 163712, China. Electronic address: 76386068@qq.com. 3. Department of Clinical Laboratory, Daqing people's Hospital, Daqing, Heilongjiang 163316, China. Electronic address: Wanghz73@163.com. 4. Department of Pediatrics, Daqing people's Hospital, Daqing, Heilongjiang 163316, China. Electronic address: mtheone@126.com. 5. Department of Psychology, College of Nursing, Harbin Medical University in Daqing, Daqing, Heilongjiang 163319, China. Electronic address: 1140504428@qq.com. 6. Department of Physiology, College of Basic Medical Sciences, Harbin Medical University in Daqing, Daqing, Heilongjiang 163319. Electronic address: 1114146577@qq.com. 7. Department of Pharmacology, College of Basic Medical Sciences, Harbin Medical University in Daqing, Daqing, Heilongjiang 163319, China. Electronic address: 437343482@qq.com. 8. Department of Pharmacology, College of Basic Medical Sciences, Harbin Medical University in Daqing, Daqing, Heilongjiang 163319, China. Electronic address: hlsun2002@163.com. 9. Department of Child and Adolescent Health, School of Public Health, Harbin Medical University, Harbin, Heilongjiang 150081, China. Electronic address: wljhyd@163.com.
Abstract
BACKGROUND: Autism spectrum disorder (ASD) is a group of extensive neurodevelopmental disorders for which few efficacious drugs are available. Sodium selenite (Se), the most common inorganic form of selenium given to humans and animals, has antioxidant, anti-inflammatory, and neuroprotective effects in several psychiatric and neurological disorders. However, the effect of Se on ASD is unclear. METHODS: Using the BTBR T + tf/J (BTBR) mouse model of ASD, we investigated the therapeutic effects and underlying mechanism of action of Se on ASD. BTBR mice were randomly divided into four groups: BTBR, BTBR+Se, BTBR+Se+ML385, and BTBR+Se+RSL3. The normal control group was composed of C57BL/6 (B6) mice. Se, Nuclear factor erythroid 2-related factor 2 (Nrf2), and glutathione peroxidase 4 (GPx4) inhibitors were administered separately for 28 days using oral gavage. After 28 days, social behavior, ferroptosis indices, and gene and protein expression levels for components of the Nrf2/GPx4 pathway were assessed to explore the correlation between Se levels and ASD. RESULTS: We demonstrated that Se significantly mitigated impairments in learning and memory, improved social functions, reduced repetitive behaviors, and inhibited ferroptosis in the CA1 area of the hippocampus. We also found that the Nrf2/GPX4 pathway was a target for Se. Treatment with Se increased levels of Nrf2 and GPX4. The Nrf2 inhibitor ML385 reduced the effect of Se on ferroptosis and abnormal behaviors in BTBR mice. In addition, the GPx4 inhibitor RSL3 revealed similar efficacy to ML385 CONCLUSION: We determined that Se exhibited a beneficial effect on autism-relevant behaviors and inhibited ferroptosis in the BTBR mouse model of ASD, possibly through modulation of the Nrf2/GPX4 signaling pathway.
BACKGROUND: Autism spectrum disorder (ASD) is a group of extensive neurodevelopmental disorders for which few efficacious drugs are available. Sodium selenite (Se), the most common inorganic form of selenium given to humans and animals, has antioxidant, anti-inflammatory, and neuroprotective effects in several psychiatric and neurological disorders. However, the effect of Se on ASD is unclear. METHODS: Using the BTBR T + tf/J (BTBR) mouse model of ASD, we investigated the therapeutic effects and underlying mechanism of action of Se on ASD. BTBR mice were randomly divided into four groups: BTBR, BTBR+Se, BTBR+Se+ML385, and BTBR+Se+RSL3. The normal control group was composed of C57BL/6 (B6) mice. Se, Nuclear factor erythroid 2-related factor 2 (Nrf2), and glutathione peroxidase 4 (GPx4) inhibitors were administered separately for 28 days using oral gavage. After 28 days, social behavior, ferroptosis indices, and gene and protein expression levels for components of the Nrf2/GPx4 pathway were assessed to explore the correlation between Se levels and ASD. RESULTS: We demonstrated that Se significantly mitigated impairments in learning and memory, improved social functions, reduced repetitive behaviors, and inhibited ferroptosis in the CA1 area of the hippocampus. We also found that the Nrf2/GPX4 pathway was a target for Se. Treatment with Se increased levels of Nrf2 and GPX4. The Nrf2 inhibitor ML385 reduced the effect of Se on ferroptosis and abnormal behaviors in BTBR mice. In addition, the GPx4 inhibitor RSL3 revealed similar efficacy to ML385 CONCLUSION: We determined that Se exhibited a beneficial effect on autism-relevant behaviors and inhibited ferroptosis in the BTBR mouse model of ASD, possibly through modulation of the Nrf2/GPX4 signaling pathway.