5-aminolevulinic acid inhibits oxidative stress and ameliorates autistic-like behaviors in prenatal valproic acid-exposed rats
5-aminolevulinic acid inhibits oxidative stress and ameliorates autistic-like behaviors in prenatal valproic acid-exposed rats
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DOI：
10.1016/j.neuropharm.2020.107975
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发表时间：
2020-05-15
影响因子：
4.7
通讯作者：
Fukunaga, Kohji
中科院分区：
文献类型：
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作者：
Matsuo, Kazuya;Yabuki, Yasushi;Fukunaga, Kohji
自闭症谱系障碍（ASD）是一种神经发育障碍，其特征是社会缺陷，重复行为和学习障碍。氧化应激和线粒体功能障碍与ASD脑病理学相关。在这里，我们使用氧化应激在产前丙戊酸（VPA）暴露大鼠作为ASD模型。母体VPA暴露后（600 mg/kg，p.o.）在胚胎第12.5天（E），使用抗4-羟基-2-壬烯醛抗体对脑中氧化应激的时间分析显示，出生后海马中的氧化应激增加。这伴随着线粒体电子传递链中的异常酶活性和海马中三磷酸腺苷（ATP）水平的降低。暴露于VPA的大鼠表现出受损的空间参考和物体识别记忆以及受损的社会行为和重复行为。通过长期口服5-氨基乙酰丙酸（5-ALA; 30 mg/kg/天）和鼻内给予催产素（OXT; 12 μ g/kg/天）（一种改善ASD患者社会行为的神经肽）来挽救ASD样行为，包括学习和记忆。5-ALA而不是OXT治疗改善VPA暴露大鼠海马的氧化应激和线粒体功能障碍。在VPA暴露的大鼠中观察到较少的小白蛋白阳性中间神经元。5-ALA和OXT治疗均增加了小清蛋白阳性中间神经元的数量。总的来说，我们的研究结果表明，口服5-ALA管理改善氧化应激和线粒体功能障碍，表明5-ALA管理改善ASD样神经病理学和行为通过不同的机制OXT。
Autism spectrum disorders (ASDs) constitute a neurodevelopmental disorder characterized by social deficits, repetitive behaviors, and learning disability. Oxidative stress and mitochondrial dysfunction are associated with ASD brain pathology. Here, we used oxidative stress in prenatal valproic acid (VPA)-exposed rats as an ASD model. After maternal VPA exposure (600 mg/kg, p.o.) on embryonic day (E) 12.5, temporal analyses of oxidative stress in the brain using an anti-4-hydroxy-2-nonenal antibody revealed that oxidative stress was increased in the hippocampus after birth. This was accompanied by aberrant enzymatic activity in the mitochondrial electron transport chain and reduced adenosine triphosphate (ATP) levels in the hippocampus. VPA-exposed rats exhibited impaired spatial reference and object recognition memory alongside impaired social behaviors and repetitive behaviors. ASD-like behaviors including learning and memory were rescued by chronic oral administration of 5-aminolevulinic acid (5-ALA; 30 mg/kg/day) and intranasal administration of oxytocin (OXT; 12 mu g/kg/day), a neuropeptide that improves social behavior in ASD patients. 5-ALA but not OXT treatment ameliorated oxidative stress and mitochondrial dysfunction in the hippocampus of VPA-exposed rats. Fewer parvalbumin-positive interneurons were observed in VPA-exposed rats. Both 5-ALA and OXT treatments augmented the number of parvalbumin-positive interneurons. Collectively, our results indicate that oral 5-ALA administration ameliorated oxidative stress and mitochondrial dysfunction, suggesting that 5-ALA administration improves ASD-like neuropathology and behaviors via mechanisms different to those of OXT.