Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children's Hospital Research Institute, Little Rock, AR 72202, USA.
Transl Psychiatry. 2012 Jul 10;2(7):e134. doi: 10.1038/tp.2012.61.
Despite increasing evidence of oxidative stress in the pathophysiology of autism, most studies have not evaluated biomarkers within specific brain regions, and the functional consequences of oxidative stress remain relatively understudied. We examined frozen samples from the cerebellum and temporal cortex (Brodmann area 22 (BA22)) from individuals with autism and unaffected controls (n=15 and n=12 per group, respectively). Biomarkers of oxidative stress, including reduced glutathione (GSH), oxidized glutathione (GSSG) and glutathione redox/antioxidant capacity (GSH/GSSG), were measured. Biomarkers of oxidative protein damage (3-nitrotyrosine; 3-NT) and oxidative DNA damage (8-oxo-deoxyguanosine; 8-oxo-dG) were also assessed. Functional indicators of oxidative stress included relative levels of 3-chlorotyrosine (3-CT), an established biomarker of a chronic inflammatory response, and aconitase activity, a biomarker of mitochondrial superoxide production. Consistent with previous studies on plasma and immune cells, GSH and GSH/GSSG were significantly decreased in both autism cerebellum (P<0.01) and BA22 (P<0.01). There was a significant increase in 3-NT in the autism cerebellum and BA22 (P<0.01). Similarly, 8-oxo-dG was significantly increased in autism cerebellum and BA22 (P<0.01 and P=0.01, respectively), and was inversely correlated with GSH/GSSG in the cerebellum (P<0.01). There was a significant increase in 3-CT levels in both brain regions (P<0.01), whereas aconitase activity was significantly decreased in autism cerebellum (P<0.01), and was negatively correlated with GSH/GSSG (P=0.01). Together, these results indicate that decreased GSH/GSSG redox/antioxidant capacity and increased oxidative stress in the autism brain may have functional consequence in terms of a chronic inflammatory response, increased mitochondrial superoxide production, and oxidative protein and DNA damage.
尽管越来越多的证据表明氧化应激在自闭症的病理生理学中起作用，但大多数研究并未评估特定脑区的生物标志物，而氧化应激的功能后果仍相对研究不足。我们检查了自闭症患者和无自闭症对照者（每组分别为 15 名和 12 名）的小脑和颞叶皮质（Brodmann 区 22（BA22））的冷冻样本。测量了氧化应激的生物标志物，包括还原型谷胱甘肽（GSH）、氧化型谷胱甘肽（GSSG）和谷胱甘肽氧化还原/抗氧化能力（GSH/GSSG）。还评估了氧化蛋白损伤的生物标志物（3-硝基酪氨酸；3-NT）和氧化 DNA 损伤的生物标志物（8-氧代-脱氧鸟苷；8-oxo-dG）。氧化应激的功能指标包括 3-氯酪氨酸（3-CT）的相对水平，3-CT 是慢性炎症反应的既定生物标志物，以及顺乌头酸酶活性，顺乌头酸酶是线粒体超氧化物产生的生物标志物。与之前关于血浆和免疫细胞的研究一致，自闭症患者的小脑（P<0.01）和 BA22（P<0.01）中 GSH 和 GSH/GSSG 均显著降低。自闭症患者的小脑和 BA22 中 3-NT 显著增加（P<0.01）。同样，自闭症患者的小脑和 BA22 中 8-oxo-dG 显著增加（P<0.01 和 P=0.01），且与小脑中的 GSH/GSSG 呈负相关（P<0.01）。两个脑区的 3-CT 水平均显著升高（P<0.01），而自闭症患者的小脑中顺乌头酸酶活性显著降低（P<0.01），且与 GSH/GSSG 呈负相关（P=0.01）。综上所述，这些结果表明，自闭症患者大脑中的 GSH/GSSG 氧化还原/抗氧化能力降低和氧化应激增加可能对慢性炎症反应、线粒体超氧化物产生增加以及氧化蛋白和 DNA 损伤产生功能后果。
