Department of Biology, College of Liberal Arts and Sciences, Tokyo Medical and Dental University, Chiba, Japan.
Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University, Tokyo, Japan.
J Pineal Res. 2021 Jan;70(1):e12703. doi: 10.1111/jpi.12703. Epub 2020 Nov 20.
Melatonin (MEL) has been reported to enhance cognitive processes, making it a potential treatment for cognitive decline. However, the role of MEL's metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in these effects are unknown. The current study directly investigated the acute effects of systemic MEL, AFMK, and AMK on novel object recognition. We also analyzed MEL, AFMK, and AMK levels in hippocampus and temporal lobe containing the perirhinal cortex following systemic MEL and AMK treatment. AMK administered post-training had a more potent effect on object memory than MEL and AFMK. AMK was also able to rescue age-associated declines in memory impairments when object memory was tested up to 4 days following training. Results from administering AMK at varying times around the training trial and the metabolism time course in brain tissue suggest that AMK's memory-enhancing effects reflect memory consolidation. Furthermore, inhibiting the MEL-to-AMK metabolic pathway disrupted object memory at 24 hours post-training, suggesting that endogenous AMK might play an important role in long-term memory formation. This is the first study to report that AMK facilitates long-term object memory performance in mice, and that MEL crosses the blood-brain barrier and is immediately converted to AMK in brain tissue. Overall, these results support AMK as a potential therapeutic agent to improve or prevent memory decline.
褪黑素 (MEL) 已被报道可增强认知过程，使其成为治疗认知能力下降的潜在方法。然而，MEL 的代谢物 N1-乙酰-N2-甲酰-5-甲氧基犬尿氨酸 (AFMK) 和 N1-乙酰-5-甲氧基犬尿氨酸 (AMK) 在这些作用中的作用尚不清楚。本研究直接研究了全身给予 MEL、AFMK 和 AMK 对新物体识别的急性影响。我们还分析了在给予全身 MEL 和 AMK 治疗后，海马体和包含边缘下皮质的颞叶中 MEL、AFMK 和 AMK 的水平。与 MEL 和 AFMK 相比，AMK 在训练后给药对物体记忆具有更强的作用。AMK 还能够在训练后长达 4 天进行物体记忆测试时挽救与年龄相关的记忆障碍。在训练试验周围的不同时间给予 AMK 和脑组织中的代谢时间过程的结果表明，AMK 的记忆增强作用反映了记忆巩固。此外，抑制 MEL 到 AMK 的代谢途径会破坏训练后 24 小时的物体记忆，表明内源性 AMK 可能在长期记忆形成中发挥重要作用。这是第一项报道 AMK 可促进小鼠长期物体记忆表现的研究，并且 MEL 穿过血脑屏障并立即在脑组织中转化为 AMK。总的来说，这些结果支持 AMK 作为一种潜在的治疗剂，以改善或预防记忆下降。
