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.
Highlights
In 2021, the journal of Science released a new edition of “125 scientific questions at the forefront of the world”
In order to investigate whether ferroptosis is involved in SDinduced memory deficits and the alleviative effect of Mel on it, we performed behavioral analysis
After Fer-1 supplementation in the sleep deprivation (SD) mice, the latency was 56.4% (p 0.001) lower than in the SD mice, the path length was 58.6% (p 0.001) shorter, the number of entries into the target zone was 212.5% (p < 0.001) higher, and the time spent there was 93.2% (p 0.032) higher, indicating that SD may induce ferroptosis, in turn leading to memory deficits
Summary
In 2021, the journal of Science released a new edition of “125 scientific questions at the forefront of the world”. One of the questions is why do we need sleep, which undoubtedly illustrates the importance of sleep for human health. With the surge of social pressure, more people choose to sacrifice sleep time to study, work and so on. This causes a series of health crises, such as cognitive impairment (Leng et al, 2017) and cardiovascular damage (Shahrbabaki et al, 2021). Researchers recently analyzed 25 years of health data from nearly 8,000 middleaged people and found a link between sleep and dementia as people get older. The current research on how sleep loss promote the occurrence of dementia is still insufficient
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