Changes in RBM47 expression based on the timing of melatonin administration and its effects on Nrf2 activity in the hippocampus

Abstract

Melatonin is an endogenous indoleamine that plays a significant role in various physiological processes, including the sleep-wake cycle, anxiety, immunity, and circadian rhythms. However, it is important to clarify that melatonin does not directly control circadian rhythms. Circadian rhythms are primarily synchronized by light, which acts on the suprachiasmatic nucleus (SCN) and subsequently regulates melatonin production. This light-mediated synchronization of circadian rhythms is essential for maintaining the alignment of the body with the light-dark cycle. In this study, we investigated the efficacy of melatonin administration during different times of the day or night and explored its neuroprotective effects. Furthermore, we aimed to apply these findings to rodent models of dementia, aging, and neuro-inflammation for potential therapeutic applications. Our study uncovered novel evidence suggesting the involvement of RNA-binding motif protein (RBM)-47 and Nrf2 in the signaling pathways associated with melatonin administration during both day and night. We examined the role of RBM47 in Nrf2 activity through siRNA or CRISPR-mediated knockdown experiments using hippocampal neuronal cells and lentivirus injections in mice. In 5xFAD/aging/neuroinflammatory mouse models, antioxidant effects were enhanced when melatonin was administered during the day compared to nighttime administration. Furthermore, mRNA analysis and molecular biology experiments revealed the differential expression of RBM47 depending on the timing of melatonin administration. These findings suggest that a decrease in RBM47 expression may improve the antioxidant defense system in the hippocampus. Consequently, administering melatonin during the day rather than at night may present a plausible therapeutic strategy as an antioxidant.