DELAYING BRAIN MITOCHONDRIAL DECAY WITH MITOCHONDRIAL ANTIOXIDANTS/METABOLITES, ACETYL-L-CARNITINE AND R-a-LIPOIC ACID IN OLD RATS
J Liu, E. Head, A Gharib, C. W. Cotman, and B. N. Ames,
Dept. Mol. Cell Biol., Univ. California, Berkeley, CA 94720, Children's Hospital Oakland Research Institute, Oakland, CA 94609; and Institute for Brain Aging and Dementia, Univ. of California, Irvine, CA 92697
The present study examined the effects of acetyl-L-carnitine (ALCAR) and R-lipoic acid, as well as their combination, on spatial memory using the Morris water maze, and an implicit memory task using the Skinner box 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, and the combination showed a larger reversal than either lipoic acid or ALCAR alone. Immunohistochemical staining showed that both nitrotyrosine (an index of oxidative protein damage) and oxo8dG/oxo8G (an index of oxidative DNA/RNA damage) increase with age in the hippocampus and cortex of rat brain while the dietary administration of ALCAR or lipoic acid reduced both oxidative biomarkers. Again, the combination showed more significant reduction of the accumulation of these oxidative metabolic by-products. In addition, the dietary administration of ALCAR or lipoic acid improved carnitine acetyltransferase substrate binding affinity and activity in old rat brain. These results suggest that these mitochondrial metabolites restore rat brain mitochondria to a more youthful state which improves brain function (Hagen et al., 2002; Liu et al., 2002a; Liu et al., 2002b; Liu et al., 2002c).
References:
Hagen, T.M., Liu, J., J., L., Wehr, C.M., Ingersoll, R.T., Vinarsky, V., Bartholomew, J.C. and Ames, B.N. (2002) Feeding Acetyl-L-carnitine combined with lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Proc. Natl. Acad. Sci. USA, (in press).
Liu, J., Atamna, H., Kuratsune, H. and Ames, B.N. (2002a) Delaying brain mitochondrial decay and aging with mitochondrial antioxidants and metabolites. Ann. New York Acad. Sci., (in press).
Liu, J., Head, E., Gharib, A.M., Yuan, W., Ingersoll, R.T., Hagen, T.M., Cotman, C.W. and Ames, B.N. (2002b) Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: Partial reversal by feeding acetyl-L-carnitine and/or R-a-lipoic acid. Proc Natl Acad Sci U S A, (in press).
Liu, J., Killilea, D. and Ames, B.N. (2002c) Age-associated mitochondrial oxidative decay: Improvement of carnitine acetyltransferase substrate binding affinity and activity in brain by feeding old rats acetyl-L-carnitine and/or R-a-lipoic acid. Proc. Natl. Acad. Sci. USA, (in press).
Key words:
brain, mitochondria, acetyl-L-carnitine, lipoic aicd, oxidative damage
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