N1-Acetyl-5-methoxyquinuramine, which decreases in the hippocampus with aging, improves long-term memory via CaMKII/CREB phosphorylation

Melatonin is a molecule ubiquitous in nature and involved in several physiological functions. In the brain, melatonin is converted to N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and then to N1-acetyl-5-methoxykynuramine (AMK), which has been reported to strongly enhance long-term object memory formation. However, the synthesis of AMK in brain tissues and the underlying mechanisms regarding memory formation remains largely unknown. In the present study, young and old individuals from a melatonin-producing strain, C3H/He mice, were employed. The amount of AMK in the pineal gland and plasma was very low compared to those of melatonin at night; conversely, in the hippocampus, the amount of AMK was higher than that of melatonin. Ido and Tdo are possible enzyme candidates for the conversion of melatonin to AFMK; we found that Ido mRNA was expressed several brain tissues whereas Tdo mRNA was expressed only in the hippocampus. The expression levels of phosphorylated cAMP response element binding protein (CREB) and PSD-95 in whole hippocampal tissue were significantly increased with AMK treatment. Before increasing in the whole tissue, CREB phosphorylation was significantly enhanced n the nuclear fraction. In Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, we found that down-regulated genes in hippocampus of old C3H/He mice were more enriched for long-term potentiation (LTP) pathway. Gene set enrichment analysis showed that LTP and neuroactive receptor interaction gene sets were enriched in hippocampus of old mice. In addition, , Ido1 and Tdo mRNA expression was significantly decreased in the hippocampus of old mice compared to young mice, and the decrease in Tdo mRNA was more pronounced than Ido1. Furthermore, there was a higher decrease in AMK levels than in melatonin levels in the hippocampus of old mice which was less than 1/10 that of young mice. In conclusion, we first demonstrated the Tdo-related melatonin to AMK metabolism in the hippocampus and suggest a novel mechanism involved in LTP and memory formation. These results support AMK as a potential therapeutic agent to prevent memory decline.