Department of Psychology, College of Nursing, Harbin Medical University in Daqing, Daqing, Heilongjiang 163319, China.
Department of Child psychiatry, Daqing Third Hospital, Daqing, Heilongjiang 163712, China.
Brain Res Bull. 2022 Jun 1;183:38-48. doi: 10.1016/j.brainresbull.2022.02.018. Epub 2022 Feb 25.
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.
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.
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.
自闭症谱系障碍（ASD）是一组广泛的神经发育障碍，目前可用的有效药物很少。亚硒酸钠（Se）是人类和动物摄入的最常见的无机硒形式，在几种精神和神经疾病中具有抗氧化、抗炎和神经保护作用。然而，Se 对 ASD 的影响尚不清楚。
我们使用 ASD 的 BTBR T + tf / J（BTBR）小鼠模型，研究了 Se 对 ASD 的治疗效果和作用机制。BTBR 小鼠被随机分为四组：BTBR、BTBR+Se、BTBR+Se+ML385 和 BTBR+Se+RSL3。正常对照组由 C57BL/6（B6）小鼠组成。使用口服灌胃分别单独给予 Se、核因子红细胞 2 相关因子 2（Nrf2）和谷胱甘肽过氧化物酶 4（GPx4）抑制剂 28 天。28 天后，评估社交行为、铁死亡指标以及 Nrf2 / GPx4 通路成分的基因和蛋白表达水平，以探讨 Se 水平与 ASD 的相关性。
我们证明 Se 显著减轻了学习和记忆障碍，改善了社会功能，减少了重复行为，并抑制了海马 CA1 区的铁死亡。我们还发现 Nrf2 / GPx4 通路是 Se 的靶点。Se 处理增加了 Nrf2 和 GPx4 的水平。Nrf2 抑制剂 ML385 降低了 Se 对 BTBR 小鼠铁死亡和异常行为的影响。此外，GPx4 抑制剂 RSL3 表现出与 ML385 类似的功效。结论：我们确定 Se 对 ASD 相关行为表现出有益的影响，并抑制了 BTBR 小鼠模型中的铁死亡，可能是通过调节 Nrf2 / GPx4 信号通路。
