Melatonin upregulates BMAL1 to attenuate chronic sleep deprivation‐related cognitive impairment by alleviating oxidative stress

Abstract

Purpose: To investigate the mechanism underlying the regulatory effect of melatonin on chronic sleep deprivation-related cognitive impairment.Methods: Chronic sleep deprivation (CSD) model was established using the MMPM method. After the model was established, melatonin receptor agonist and inhibitor were given, respectively. Water maze was conducted to record the escape latency and the duration of crossing the platform of space exploration. The concentration of TNF-α, IL-6, MDA, and SOD was measured by ELISA. Immunofluorescence was used to determine the expression level of CD86 and CD206, while the mRNA expression of Bax, Bcl-2, P65, IκB, and BMAL1 was detected by qPCR. Western blotting assay was utilized to determine the protein expression of Bax, Bcl-2, P65, p-P65, IκB, p-I κB, and BMAL1.Results: Compared with the control, the escape latency was greatly increased on the second and third day, accompanied by the increased expression of TNF-α, IL-6, MDA, and SOD in serum. Furthermore, dramatically upregulated Bax, Bcl-2, P65, IκB, and CD86 were observed in the model group, accompanied by the declined expression level of BMAL1 and CD206. Compared with the model group, the escape latency was declined, the concentration of TNF-α, IL-6, MDA, and SOD was decreased, the expression level of Bax, Bcl-2, P65, IκB, and CD86 was declined, and the level of BMAL1 and CD206 was promoted by the treatment of the melatonin agonist, while the opposite results were observed under the treatment of the melatonin inhibitor. Conclusion:Melatonin upregulates BMAL1 to attenuate chronic sleep deprivationrelated cognitive impairment by alleviating oxidative stress.

Sleep and Oxidative Stress: Current Perspectives on the Role of NRF2

“…SIRT1, a deacetylase enzyme, plays a key role in regulating the central circadian rhythm in the SCN by promoting the transcription of the main circadian regulators, BMAL1 and CLOCK. These circadian regulators are also regulated by melatonin to alleviate oxidative stress and attenuate cognitive impairment after sleep deprivation (Chang and Guarente 2013 ; Hu et al 2023 ). Farnesol, a natural sesquiterpenoid, exerts neuroprotective effects against sleep deprivation-induced cognitive impairment by activating the SIRT1/NRF2 signaling pathway.…”

The Devastating Effects of Sleep Deprivation on Memory: Lessons from Rodent Models

“…These lesional effects are closely associated with neuritis caused by excessive microglial activation [ 32 ]. Chronic SD promotes the transformation of microglia into the neurotoxic M1 phenotype and subsequently induces the NF-κB pathway to increase the release of pro-inflammatory factors (TNF-α, IL-6), causing neuroinflammatory response, aggravating hippocampal neuron damage, and affecting cognitive function [ 55 ]. Further studies found that SD increased the protein levels of the pro-inflammatory cytokines TNF-α, IL1-β, IL-6, and IL-8 but decreased the protein levels of the anti-inflammatory cytokines IL-4 and IL-10 in the rat hippocampus [ 55 , 57 , 102 , 103 , 104 ].…”

“…Chronic SD promotes the transformation of microglia into the neurotoxic M1 phenotype and subsequently induces the NF-κB pathway to increase the release of pro-inflammatory factors (TNF-α, IL-6), causing neuroinflammatory response, aggravating hippocampal neuron damage, and affecting cognitive function [ 55 ]. Further studies found that SD increased the protein levels of the pro-inflammatory cytokines TNF-α, IL1-β, IL-6, and IL-8 but decreased the protein levels of the anti-inflammatory cytokines IL-4 and IL-10 in the rat hippocampus [ 55 , 57 , 102 , 103 , 104 ]. Serum levels of pro-inflammatory cytokines (IL-6, IL-1β, TNF-α) increased in SD rats after 24 h of SD, and the effect was more significant in cerebrospinal fluid after 72 h of SD (IL-1β: 30.2 ± 12.8 pg·mL −1 →43.6.8 ± 9.4 pg·mL −1 ; IL-6: 28.8 ± 9.3 pg·mL −1 →37.8 ± 7.4 pg·mL −1 ; TNF-α:19.1 ± 6.3 pg·mL −1 →21.8 ± 7.4 pg·mL −1 ).…”

“…Several studies have linked SD-induced memory impairment to increased oxidative stress within the hippocampus [ 55 , 63 , 113 , 114 ]. Memory formation is critically affected by oxidative stress [ 115 ].…”

“…The increased oxidative stress caused by CSD impairs short-term and long-term memory [ 116 , 117 , 118 ]. CSD also downregulates BMAL1 expression and induces excessive oxidative stress [ 55 ]. SD significantly increased the ROS, MDA, and MPO levels in the hippocampus of mice and decreased the activities of SOD, GPx, GSH, and GSH-Px enzymes.…”