Department of Child and Adolescent Health, School of Public Health, Harbin Medical University, Harbin, Heilongjiang, China; Department of Nursing, Daqing campus of Harbin Medical University, Daqing, Heilongjiang, China.
Department of Nursing, Daqing campus of Harbin Medical University, Daqing, Heilongjiang, China.
J Nutr Biochem. 2019 Sep;71:98-109. doi: 10.1016/j.jnutbio.2019.05.002. Epub 2019 Jun 18.
The aim of this study was to examine the effects of folic acid (FA) on the autistic phenotypes in BTBR T+ Itpr3tf/J (BTBR) mice and to investigate underlying mechanisms. Mice received FA (0.2 mg/kg/day) orally from postnatal days 14 to 35. Mice were then tested for stereotyped and repetitive behaviors, social interaction, and spatial learning and memory at the end of FA supplementation. Oxidative stress, neuroinflammatory responses and ferroptosis-related proteins in the brain were also evaluated. FA supplementation in BTBR mice reduced repetitive and stereotyped behavior, improved social communication, and enhanced memory and spatial learning. FA supplementation also reduced neuronal loss in hippocampal CA1 regions of the brain and decreased the levels of the proinflammatory cytokines such as interleukin-1β (IL-1β), Iba-1, IL-18, tumor necrosis factor-a, and IL-6 and glial fibrillary acidic protein in the hippocampus. FA supplementation changed the malondialdehyde and glutathione levels and superoxide dismutase (SOD) and glutathione peroxidase activities in the hippocampus. FA supplementation inhibited the elevation of the SOD1 and TFR protein levels and enhanced the relative expression levels of glutathione peroxidase 4 and ferroportin 1 in the hippocampus and increased the relative levels of phospho-Ca2+/calmodulin-dependent protein kinase II and phospho-cAMP-response element binding protein in the hippocampus. FA oral supplementation to BTBR mice rescued stereotyped and repetitive behaviors, social deficit, and spatial learning and memory impairments, likely by improving the oxidative-stress and inflammatory responses by altering the ferroptosis signaling pathways.
本研究旨在探讨叶酸（FA）对 BTBR T+ Itpr3tf/J（BTBR）小鼠自闭症表型的影响，并探讨其潜在机制。小鼠从出生后第 14 天至 35 天每天口服给予 FA（0.2mg/kg）。在 FA 补充结束时，对小鼠进行刻板和重复行为、社交互动以及空间学习和记忆测试。还评估了大脑中的氧化应激、神经炎症反应和铁死亡相关蛋白。FA 补充剂可减少 BTBR 小鼠的刻板和重复行为，改善社交交流，并增强记忆和空间学习能力。FA 补充还减少了海马 CA1 区的神经元丢失，并降低了海马中促炎细胞因子如白细胞介素-1β（IL-1β）、Iba-1、IL-18、肿瘤坏死因子-α和 IL-6 和神经胶质纤维酸性蛋白的水平。FA 补充改变了海马中的丙二醛和谷胱甘肽水平以及超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶的活性。FA 补充抑制了 SOD1 和 TFR 蛋白水平的升高，并增强了海马中谷胱甘肽过氧化物酶 4 和铁蛋白 1 的相对表达水平，并增加了海马中磷酸钙/钙调蛋白依赖性蛋白激酶 II 和磷酸 cAMP 反应元件结合蛋白的相对水平。FA 口服补充到 BTBR 小鼠中，通过改变铁死亡信号通路，挽救了刻板和重复行为、社交缺陷以及空间学习和记忆障碍。
