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In the brain, melatonin is converted to N1\u2010acetyl\u2010N2\u2010formyl\u20105\u2010methoxykynuramine (AFMK)\u00a0and then to N1\u2010acetyl\u20105\u2010methoxykynuramine (AMK),\u00a0which has been reported to strongly enhance long\u2010term object memory formation. However, the synthesis of AMK in brain tissues and the underlying mechanisms regarding memory formation remain largely unknown. In the present study, young and old individuals from a melatonin\u2010producing strain, C3H\/He mice, were employed. The amount of AMK in the pineal gland and plasma was very low compared with those of melatonin at night; conversely, in the hippocampus, the amount of AMK was higher than that of melatonin. <jats:italic>Indoleamine 2, 3\u2010dioxygenase<\/jats:italic> (<jats:italic>Ido<\/jats:italic>) mRNA was expressed in multiple brain tissues, whereas <jats:italic>tryptophan 2,3\u2010dioxygenase<\/jats:italic> (<jats:italic>Tdo<\/jats:italic>) mRNA was expressed only in the hippocampus, and its lysate had melatonin to AFMK conversion activity, which was blocked by the TDO inhibitor. The expression levels of phosphorylated cAMP response element binding protein (CREB)\u00a0and PSD\u201095\u00a0in whole hippocampal tissue were significantly increased with AMK treatment. Before increasing in the whole tissue, CREB phosphorylation was significantly enhanced in the nuclear fraction. In the Kyoto Encyclopedia of Genes and Genomes (KEGG)\u00a0pathway analysis, we found that downregulated genes in hippocampus of old C3H\/He mice were more enriched for long\u2010term potentiation (LTP)\u00a0pathway. Gene set enrichment analysis showed that LTP and neuroactive receptor interaction gene sets were enriched in hippocampus of old mice. In addition, <jats:italic>Ido1<\/jats:italic> and <jats:italic>Tdo<\/jats:italic> mRNA expression was significantly decreased in the hippocampus of old mice compared with young mice, and the decrease in <jats:italic>Tdo<\/jats:italic> mRNA was more pronounced than <jats:italic>Ido1<\/jats:italic>. Furthermore, there was a higher decrease in AMK levels, which was less than 1\/10 that of young mice, than in melatonin levels in the hippocampus of old mice. In conclusion, we first demonstrated the Tdo\u2010related melatonin to AMK metabolism in the hippocampus and suggest a novel mechanism of AMK involved in LTP and memory formation. These results support AMK as a potential therapeutic agent to prevent memory decline.<\/jats:p>","DOI":"10.1111\/jpi.12934","type":"journal-article","created":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T10:05:26Z","timestamp":1705053926000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["N1\u2010Acetyl\u20105\u2010methoxykynuramine, which decreases in the hippocampus with aging, improves long\u2010term memory via CaMKII\/CREB phosphorylation"],"prefix":"10.1111","volume":"76","author":[{"given":"Kazuki","family":"Watanabe","sequence":"first","affiliation":[{"name":"Department of Clinical Engineering, Faculty of Health Sciences Komatsu University Komatsu Ishikawa Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Maruyama","sequence":"additional","affiliation":[{"name":"Department of Sport and Wellness, College of Sport and Wellness Rikkyo University Niiza Saitama 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