Memory can be improved by Melatonin and its derivatives

Melatonin and its derivatives have been shown in animal experiments to improve memory. It is also known that the phosphorylation of specific memory-related proteins is required for the formation of both short- and long-term memories. However, the molecular mechanisms behind melatonin-induced memory enhancement remain unknown. Now, in a recent study published in NeuroReport on June 7, 2023, medical experts from Sophia University in Japan have uncovered key discoveries that add greatly to the understanding of the underlying mechanisms.

The study’s lead author Professor Atsuhiko Chiba from the Department of Materials and Life Sciences, Faculty of Science and Technology, Sophia University mentioned “Our study aimed to investigate the effects of melatonin, ramelteon, and N1-acetyl-5-methoxyquinuramine on the relative phosphorylation levels of memory-related proteins in order to explore candidate signaling pathways associated with the receptor- and nonreceptor-mediated memory-enhancing effects of melatonin.

Dr. Masahiro Sano (currently affiliated with Tohoku University) and Dr. Hikaru Iwashita (currently affiliated with Kansai Medical University), who happen to be a major part of the research team have studied the effects of three compounds on the formation of memory; melatonin, a hormone secreted by the pineal gland in the brain; N1-acetyl-5-methoxyquinuramine (AMK), a metabolic metabolite of melatonin; and ramelteon, a medication that binds to and activates the melatonin receptor.

Furthermore, scientists looked at “phosphorylation,” which is the biological addition of phosphate groups to protein structures, in five critical proteins involved in memory formation. Extracellular signal-regulated kinase (ERK), calcium/calmodulin-dependent kinase II (CaMKII), CaMKII, CaMKIV, and the cAMP-response element binding protein (CREB) were among them.

Initial studies on male mice clearly shown that treatment of melatonin, ramelteon, or AMK at a level of 1 mg/kg aided in the establishment of long-term memory. The researchers did not test the effects of the three chemicals on female mice in order to avoid data variability caused by the reproductive cycles of female mammals.

Long-term memory formation in male mice was evaluated using a series of tests based on the new objection recognition task, or “NORT.” In this work, laboratory mice were first acclimated to an experimental arena for five minutes every day for three days in a row. On the fourth day, mice were allowed to investigate two similar objects in the experimental arena for five minutes (training phase).

The male mice were tested twenty-four hours after the training phase was completed. One of the two familiar things was swapped with a new or unknown object throughout the testing phase. A trained observer recorded the length of time the mice spent examining each object, which is an excellent indication of object recognition memory. It is well known that mice spend more time examining unfamiliar objects and less time approaching familiar objects.

After executing the rodents using conventional techniques, the researchers investigated the effects of ramelteon and AMK on the phosphorylation of ERK, CaMKII, CaMKII, CaMKIV, and CREB in the male mouse brain. Ramelteon/AMK therapy greatly elevated phosphorylation of both ERK and CREB in the hippocampus, the mammalian brain’s learning and memory center.

These medicines, however, significantly reduced CaMKII/ phosphorylation in the same brain region. Both ramelteon and AMK significantly enhanced ERK in the perirhinal cortex (PRC), which is similarly connected with memory processes, but only ramelteon significantly increased CaMKII phosphorylation. Ramelteon/AMK had no effect on CaMKIV phosphorylation in the hippocampus/PRC.

“Our findings suggest that melatonin is involved in promoting the formation of long-term object recognition memory by modulating the phosphorylation levels of memory-related proteins such as ERK, CaMKIIs, and CREB in both receptor-mediated and nonreceptor-mediated signaling pathways.” says Prof. Chiba while concluding.

The researchers hope that the findings of their study may aid in the development of novel medications that can improve memory function in persons suffering from age-related memory decline while having fewer negative effects.

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