Melatonin Alleviates Cognitive Impairment Caused By Chronic Intermittent Hypoxia Through Enhances Autophagy And Inhibiting NLRP3 Inflammasome Activation

Background: The main clinical manifestation of obstructive sleep apnea in neurological complications is cognitive dysfunction.At the same time,the inflammatory cascade mediated by NOD-like receptor protein 3(NLRP3)plays an important role in cognitive dysfunction.Autophagy refers to a process in which components such as own cell proteins and damaged organelles are encapsulated in double-layer membrane vesicles and transported to lysosomes for degradation.The change of autophagy activity is closely related to cognitive function,and melatonin has a protective effect on cognitive function.In recent years,their relationship has attracted much attention,and its specific mechanism remains to be studied.Objective:We investigate the mechanism that the melatonin reduces cognitive impairment caused by CIH were related to enhancing autophagy activity and inhibiting NLRP3 inflammasome activation mode.Methods: The mice were randomly divided into four groups,which are namely normoxia group(NC),chronic intermittent hypoxia group(CIH),CIH+melatonin group(CIH+Mel),CIH+Mel+3-methyladenine group(CIH+Mel+3-MA).The mice were exposed to normoxia or CIH for 8 hours in 7 weeks,the Apnea Hyponea Index(AHI)was 30 beats/h.Morris water maze detected the cognitive function of mice.Then immunohistochemistry was used to detect the histological morphological changes of hippocampus;quantitative real time PCR(RT-q PCR)was used to detect the m RNA expression of autophagy-related factors p62 and Beclin-1 in hippocampus;Western blotting(WB)to detect the protein expression levels of SIRT1、p62、LC3B and NLRP3 inflammasomes 、caspase-1、IL1β、IL18 in hippocampal tissue.Results: CIH can induce cognitive dysfunction,activate NLRP3 inflammasome in hippocampus and enhance autophagy.Melatonin can significantly improve the cognitive function of mice,inhibit the inflammatory response mediated by NLRP3 inflammasome,and enhance the autophagy activity.However,the inhibitory effect of melatonin on the activation of NLRP3 inflammasome was blocked by 3-m A.Conclusion: Melatonin can inhibit the inflammatory response mediated by NLRP3 inflammasome by increasing the autophagy activity,thereby reducing the cognitive impairment caused by CIH.