Liu Jiankang, Head Elizabeth, Gharib Afshin M, Yuan Wenjun, Ingersoll Russell T, Hagen Tory M, Cotman Carl W, Ames Bruce N
Division of Biochemistry and Molecular Biology, University of California, Berkeley, CA 94720, USA.
Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):2356-61. doi: 10.1073/pnas.261709299.
Accumulation of oxidative damage to mitochondria, protein, and nucleic acid in the brain may lead to neuronal and cognitive dysfunction. The effects on cognitive function, brain mitochondrial structure, and biomarkers of oxidative damage were studied after feeding old rats two mitochondrial metabolites, acetyl-l-carnitine (ALCAR) [0.5% or 0.2% (wt/vol) in drinking water], and/or R-alpha-lipoic acid (LA) [0.2% or 0.1% (wt/wt) in diet]. Spatial memory was assessed by using the Morris water maze; temporal memory was tested by using the peak procedure (a time-discrimination procedure). Dietary supplementation with ALCAR and/or LA improved memory, the combination being the most effective for two different tests of spatial memory (P < 0.05; P < 0.01) and for temporal memory (P < 0.05). Immunohistochemical analysis showed that oxidative damage to nucleic acids (8-hydroxyguanosine and 8-hydroxy-2'-deoxyguanosine) increased with age in the hippocampus, a region important for memory. Oxidative damage to nucleic acids occurred predominantly in RNA. Dietary administration of ALCAR and/or LA significantly reduced the extent of oxidized RNA, the combination being the most effective. Electron microscopic studies in the hippocampus showed that ALCAR and/or LA reversed age-associated mitochondrial structural decay. These results suggest that feeding ALCAR and LA to old rats improves performance on memory tasks by lowering oxidative damage and improving mitochondrial function.
大脑中线粒体、蛋白质和核酸的氧化损伤积累可能导致神经元和认知功能障碍。给老年大鼠喂食两种线粒体代谢物，即乙酰 - L - 肉碱（ALCAR）[饮用水中0.5%或0.2%（重量/体积）]和/或R - α - 硫辛酸（LA）[饮食中0.2%或0.1%（重量/重量）]后，研究了其对认知功能、脑线粒体结构以及氧化损伤生物标志物的影响。通过莫里斯水迷宫评估空间记忆；通过峰值程序（一种时间辨别程序）测试时间记忆。饮食中补充ALCAR和/或LA可改善记忆，二者组合对空间记忆的两种不同测试（P < 0.05；P < 0.01）和时间记忆（P < 0.05）最为有效。免疫组织化学分析表明，核酸（8 - 羟基鸟苷和8 - 羟基 - 2'-脱氧鸟苷）的氧化损伤在海马体中随年龄增加，海马体是对记忆很重要的区域。核酸的氧化损伤主要发生在RNA中。饮食给予ALCAR和/或LA显著降低了氧化RNA的程度，二者组合最为有效。海马体的电子显微镜研究表明，ALCAR和/或LA逆转了与年龄相关的线粒体结构衰退。这些结果表明，给老年大鼠喂食ALCAR和LA可通过降低氧化损伤和改善线粒体功能来提高记忆任务的表现。
