NYS Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA.
Neurochem Res. 2012 Aug;37(8):1681-9. doi: 10.1007/s11064-012-0775-4. Epub 2012 Apr 12.
Autism is a heterogeneous, behaviorally defined neurodevelopmental disorder. Recently, we reported a brain region-specific increase in lipid peroxidation, and deficits in mitochondrial electron transport chain complexes in autism, suggesting the role of oxidative stress and mitochondrial dysfunction in the pathophysiology of autism. However, the antioxidant status of the brain is not known in autism. Glutathione is a major endogenous antioxidant that plays a crucial role in protecting cells from exogenous and endogenous toxins, particularly in the central nervous system. The present study examines the concentrations of glutathione (GSH, reduced form; and GSSG, oxidized form) and the redox ratio of GSH to GSSG (marker of oxidative stress) in different regions of brains from autistic subjects and age-matched control subjects. In the cerebellum and temporal cortex from subjects with autism, GSH levels were significantly decreased by 34.2 and 44.6 %, with a concomitant increase in the levels of GSSG by 38.2 and 45.5 %, respectively, as compared to the control group. There was also a significant decrease in the levels of total GSH (tGSH) by 32.9 % in the cerebellum, and by 43.1 % in the temporal cortex of subjects with autism. In contrast, there was no significant change in GSH, GSSG and tGSH levels in the frontal, parietal and occipital cortices in autism versus control group. The redox ratio of GSH to GSSG was also significantly decreased by 52.8 % in the cerebellum and by 60.8 % in the temporal cortex of subjects with autism, suggesting glutathione redox imbalance in the brain of individuals with autism. These findings indicate that autism is associated with deficits in glutathione antioxidant defense in selective regions of the brain. We suggest that disturbances in brain glutathione homeostasis may contribute to oxidative stress, immune dysfunction and apoptosis, particularly in the cerebellum and temporal lobe, and may lead to neurodevelopmental abnormalities in autism.
自闭症是一种异质性的、行为定义的神经发育障碍。最近，我们报道了自闭症患者大脑特定区域脂质过氧化增加，以及线粒体电子传递链复合物缺陷，这表明氧化应激和线粒体功能障碍在自闭症的病理生理学中起作用。然而，自闭症患者大脑中的抗氧化状态尚不清楚。谷胱甘肽是一种主要的内源性抗氧化剂，在保护细胞免受外源性和内源性毒素的侵害方面发挥着至关重要的作用，尤其是在中枢神经系统中。本研究检测了自闭症患者和年龄匹配的对照组不同脑区的谷胱甘肽（还原形式 GSH 和氧化形式 GSSG）浓度以及 GSH 与 GSSG 的氧化还原比（氧化应激标志物）。与对照组相比，自闭症患者小脑和颞叶皮层的 GSH 水平分别显著下降了 34.2%和 44.6%，GSSG 水平分别显著升高了 38.2%和 45.5%。自闭症患者小脑的总谷胱甘肽（tGSH）水平也显著下降了 32.9%，颞叶皮层下降了 43.1%。相比之下，自闭症患者额叶、顶叶和枕叶皮层的 GSH、GSSG 和 tGSH 水平没有显著变化。自闭症患者小脑和颞叶皮层的 GSH 与 GSSG 的氧化还原比也分别显著下降了 52.8%和 60.8%，提示自闭症患者大脑中谷胱甘肽氧化还原失衡。这些发现表明自闭症与大脑中特定区域谷胱甘肽抗氧化防御能力下降有关。我们认为，大脑谷胱甘肽动态平衡的紊乱可能导致氧化应激、免疫功能障碍和细胞凋亡，尤其是在小脑和颞叶，这可能导致自闭症的神经发育异常。
