Melatonin improves D-galactose-induced aging effects on behavior, neurogenesis, and lipid peroxidation in the mouse dentate gyrus via increasing pCREB expression.

Melatonin (N-acetyl-5-methoxytryptamine) has multiple functions. In this study, we investigated the effects of melatonin on memory, cell proliferation, and neuroblast differentiation in the dentate gyrus of a mouse model of D-galactose-induced aging. D-galactose was subcutaneously administered to 7-wk-old mice for 10 wk, and age-matched mice were used as controls. Seven weeks after D-galactose administration, vehicle (water) or melatonin (6 mg/L in water) was administered ad libitum to the mice for 3 wk. The administration of D-galactose significantly increased the escape latency compared with that in the control mice on days 1-3. In addition, cells in the subgranular zone and in the granule cell layer of the dentate gyrus showed severe damage (cytoplasmic condensation) in the D-galactose-treated mice. However, melatonin supplementation to these mice for 3 wk significantly ameliorated the D-galactose-induced increase in escape latency and neuronal damage compared with the vehicle-treated group. The administration of melatonin also significantly restored the D-galactose-induced reduction of proliferating cells (Ki67-positive cells) and differentiating neuroblasts (doublecortin-positive neuroblasts) in the dentate gyrus. Furthermore, the administration of melatonin significantly increased Ser133-phosphorylated cyclic AMP response element binding protein in the dentate gyrus. The administration of melatonin significantly reduced D-galactose-induced lipid peroxidation in the dentate gyrus. These results suggest that melatonin may be helpful in reducing age-related phenomena in the brain.