MITOCHONDRIAL METABOLITES, ACETYL-L-CARNITINE AND LIPOIC ACID, IMPROVE AGE-ASSOCIATED MEMORY DECLINE AND INHIBIT BRAIN OXIDATIVE DAMAGE IN OLD RATS
J. Liu, A. Gharib, E. Head, C. W. Cotman, and B. N. Ames
Division of Biochemistry and Molecular Biology, University of California, Berkeley, CA 94720 and Children’s Hospital Oakland Research Institute, Oakland, CA 94609
To extend our previous study of acetyl-L-carnitine (ALCAR) (Hagen, T. et al: PNAS 95:9562-6, 1998) and lipoic acid (Hagen, T. et al.: FASEB13:411-8, 1999) on the mitochondrial function in the liver of old rats to the brain function, the present study examined the effects of ALCAR and lipoic acid as well as their combination on spatial memory with Morris water maze test, and an IQ-related implicit memory with Skinner box test in old rats. Both ALCAR and lipoic acid showed effects in improving the age-associated memory decline, and the combination showed a more significant improvement in both memory tests. Electron microscopic observation demonstrated that ALCAR, lipoic acid, or their combination reversed the age-associated decay of mitochondrial structure in brain hippocampus, whereas the combination showed larger reverse than either lipoic acid or ALCAR alone. Immunohistochemical staining showed that both nitrotyrosine (an index of oxidative protein damage) and oxo8G/dG (an index of oxidative RNA/DNA damage) increase with age in the hippocampus and cortex of rat brain while the dietary administration of ALCAR or/and lipoic acid showed inhibition of both oxidative biomarkers. These results suggest that the memory improving effects of these mitochondrial metabolites in rats may be through an antioxidant mechanism, possibly by scavenging oxidants, maintaining mitochondrial membrane integrity and mitochondrial function, or clearing out the accumulation of oxidative metabolic by-products in the brain.
Key words:
Mitochondra, RNA/DNA oxidation, memory, antioxidants
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