Melatonin and its Metabolites Supports Long-term Memory and Cognition in Mice

by | Mar 16, 2021 | 2021, Brain Health, Cognitive Health, Melatonin

Written by Joyce Smith, BS. Study suggests that melatonin (MEL) and its metabolites promote the formation of long-term memories in mice and protect against cognitive decline.

Melatonin (MEL) is produced and secreted primarily by the pineal gland. It is known for its key regulatory role in circadian rhythms and may have a role in regulating memory formation as well 1,2.

MEL is converted to the metabolites N1-acetyl-N2-formyl-5- methoxykynuramine (AFMK) and then to N1-acetyl-5- methoxykynuramine (AMK) in the brain 3. Previous studies have shown that supplementation with MEL supports certain aspects of cognition in elderly people 4 and in animal models of AD5,  such as AD, Down syndrome, sleep deprivation, and chemically induced memory impairments 5. MEL and it metabolites have anti-inflammatory, anti-amyloidogenic, and antioxidant properties 5,6 that may help reduce brain damage and improve learning and memory 5.

The current study by Iwashita and colleagues 7 hypothesized an association between supplementation with MEL and the effect of its metabolites on learning and long term memory. They investigated the effects of injecting young and old mice with MEL (and its metabolites AFMK, and AMK) on novel object recognition (NOR) to assess levels of cognitive improvement 8. In addition, they analyzed MEL, AFMK, and AMK levels in the hippocampus and temporal lobes of mice following treatment with MEL and AMK.

To test their hypothesis, the researchers used NOR 8, designed to test for memory levels, on both young and older mice. The process involved familiarizing mice to objects, then injecting them intraperitoneally with varying doses of MEL followed by the two metabolites one hour later, and testing their memory on the following day or days later. Mice have a natural tendency to examine unfamiliar objects and will spend more time checking them out than objects they are familiar with. Cognitive decline manifests as poor memory and is evident when the mice behave as if objects are new and unfamiliar to them.

After experimenting with numerous memorization training trials followed by MEL injections and different NOR testing times, researchers found that memory improvement did indeed occur in the mice and that AMK was the more effective of the two MEL metabolites in improving memory. Examination of brain tissue post-euthanization revealed that MEL crosses the blood-brain barrier, converts to AFMK, then AMK, and accumulates in the hippocampus of the brain where memory encoding and consolidation transpire. Researchers found that AMK can facilitate LTM when administered over a broad spectrum of time, but the effects are dose-dependent and lower doses are more sensitive; for example, AMK, at a 0.01 mg/kg dose, enhanced memory only when given 0 and 15 minutes post training. A single treatment with MEL or its metabolites, AFMK and AMK, remarkably improved LTM in young and middle-aged mice. Exposing them to an object just three times throughout the day established sufficient memory to enable memory recall with the next day’s NOR test (P < .05 and P < .01). This was in sharp contrast to the older mice, who, when treated with the same AMK dose, demonstrated no significant observable effects and behaved as if both objects were new and unfamiliar, an indication of cognitive decline. However, a stronger dose of one mg/kg of AMK administered after a single one minute training trial enhanced object memory in all age groups, enabling older mice to remember the objects up to 4 days later. Researchers believed that administering MEL, AFMK, and AMK to mice after training improved learning and memory because of the LTM-enhancing effects of MEL that supported memory and consolidation in the hippocampus of the brain, where short-term memory (STM) becomes LTM.

This is the first study to report that AMK facilitates long-term “object memory performance” in mice. The ability of MEL to cross the blood-brain barrier where it immediately converts to AMK in the brain suggests that AMK has the potential to become a therapeutic agent to improve quality of life in individuals with mild cognitive improvement.

Source: Iwashita, Hikaru, Yukihisa Matsumoto, Yusuke Maruyama, Kazuki Watanabe, Atsuhiko Chiba, and Atsuhiko Hattori. “The melatonin metabolite N1‐acetyl‐5‐methoxykynuramine facilitates long‐term object memory in young and aging mice.” Journal of Pineal Research 70, no. 1 (2021): e12703.

© 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Click here to read the full text study.

Posted March 16, 2021.

Joyce Smith, BS, is a degreed laboratory technologist. She received her bachelor of arts with a major in Chemistry and a minor in Biology from  the University of Saskatchewan and her internship through the University of Saskatchewan College of Medicine and the Royal University Hospital in Saskatoon, Saskatchewan. She currently resides in Bloomingdale, IL.

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