Melatonin Alleviates Acute Sleep Deprivation-Induced Memory Loss in Mice by Suppressing Hippocampal Ferroptosis

Abstract

Objectives: Memory decline caused by insufficient sleep is a critical public health issues and currently lacks effective treatments. This study objective was to explore alleviative effect of melatonin on sleep deprivation (SD)-induced deficiencies in learning and memory.Materials and Methods: A continuous 72 h SD mouse model, with or without melatonin or Fer-1 supplementation were established. The changes of cognitive function, iron homeostasis, lipid peroxidation and intracellular signal pathways in mice were detected by Morris water maze, antioxidant assay, immunohistochemistry, western blot, RT-PCR and Prussian blue staining. In vitro, we treated HT-22 cells with ferroptosis inducer (Erastin) to further explore the specific mechanism of melatonin in ferroptosis.Results: Mice subjected to SD had significantly elevated latency and path length to reach hidden platform, as well as a decrease in number of entries and time spent in the target zone when the hidden platform was removed (p < 0.05). Nevertheless, supplementation with ferroptosis inhibitor (Fer-1) mitigated the memory impairment associated with SD. Further evaluation revealed an up-regulation of intracellular iron accumulation, transferrin receptor 1 and divalent metal transporter 1 expression and ROS and MDA production, and a down-regulation of ferroportin and antioxidant enzyme (GPX4 and SOD) expression in SD mice. SD decreased expression of MT2 receptor rather than of MT1, and inhibited ERK/Nrf2 signaling activation in the hippocampus (p < 0.05). In contrast, the aforementioned SD-inductions were reversed by supplementation using 20 and 40 mg/kg melatonin in SD mice. In vitro, melatonin pretreatment reversed Erastin-induced ferroptosis, abnormalities in iron transporter protein and antioxidant enzyme expression and suppression of ERK/Nrf2 signaling in HT-22 cells, however this protective effect of melatonin was blocked by MT2-, ERK- and Nrf2-specific antagonists (p < 0.05).Conclusion: Our finding suggested SD may induce ferroptosis, in turn leading to cognitive deficits. Melatonin alleviated memory loss and hippocampal ferroptosis caused by acute SD through binding to the MT2 receptor to activate ERK/Nrf2 signaling.

Ketogenic diet prevents chronic sleep deprivation-induced Alzheimer’s disease by inhibiting iron dyshomeostasis and promoting repair via Sirt1/Nrf2 pathway

“…Growing evidence has demonstrated that SD induces cognitive impairment which also is the clinical characteristic of AD ( Zhao et al, 2017 ; Wang X. et al, 2021 ). The parameters of the MWM test showed that the escape latency was markedly increased, whereas the numbers of platform crossing and the times spent in the target phase in probe trials were obviously reduced in SD group mice.…”

“…Growing evidence demonstrates that hippocampal damage is the main factor of SD-induced cognitive dysfunction ( Zuo et al, 2020 ; Wang X. et al, 2021 ). Our present results showed that hippocampal neurons are characterized by pyknotic nuclei and vacuolated cytoplasm in SD group mice ( Figure 4A ).…”

“…Emerging evidence indicated that SD-induced cognitive deficiency can be improved by Fer-1, a specific inhibitor of ferroptosis in mice, indicating ferroptosis involved in the mechanism of SD-induced cognitive deficiency ( Wang X. et al, 2021 , 2022 ). In addition, our previous study found that KD could improve chronic SD-induced hippocampal damage by inhibiting ferroptosis in younger mice (7-week-old).…”

“…Current research indicates that ferroptosis is linked to a variety of neurodegenerative diseases, including AD ( Reichert et al, 2020 ). In addition, emerging evidence has reported that SD-caused memory impairment is related to hippocampal ferroptosis and can be reversed by ferrostatin-1, a specific inhibitor of ferroptosis ( Wang X. et al, 2021 , 2022 ). The above studies show that ferroptosis can act as a bridge between SD and AD, and targeting ferroptosis may be an effective means of preventing AD.…”

Targeting Oxidative Stress Involved in Endometriosis and Its Pain

“…Melatonin can act as a free-radical scavenger for hydrogen peroxide and nitric oxide (NO) and it also stimulates antioxidant enzymes [ 136 ]. Melatonin has also been shown to decrease lipid peroxidation and markers of ferroptosis [ 137 , 138 ]. Due to these properties, treatment of endometriosis with melatonin should protect lipids, proteins, and DNA from free-radical damage.…”