Melatonin pretreatment prevents isoflurane-induced cognitive dysfunction by modulating sleep–wake rhythm in mice

Sleep plays an important role in memory processing. However, its role in anesthesia-induced cognitive dysfunction was not revealed. Our study sought to investigate the connection between the cognition decline and sleep–wake rhythm disorders after long-term isoflurane anesthesia in mice. Also, we examined the effect of exogenous melatonin pretreatment on both cognitive function and circadian rhythm. Furthermore, we discussed whether NR2B (N-methyl–D-aspartate receptor 2B subunit)–CREB (cAMP-response element binding protein) signaling pathway was involved in this course. 2-month-old male C57/BL-6J mice were submitted to long-term anesthesia using 1% isoflurane from CT (Circadian Time) 14 to CT20. Melatonin pretreatment were conducted before anesthesia for 7 Days. Intellicage for mice and Mini-Mitter were applied to monitor spatial memory and gross motor activity which can reflect cognition and sleep–wake rhythm. Messenger RNA and protein expression of right hippocampus NR2B and CREB were examined by RT-PCR and Western blot. 6 h isoflurane anesthesia led to impaired spatial memory from Day 3 to Day 10 in mice accompanied by the disruption of sleep–wake rhythm. Meanwhile, the hippocampus CREB and NR2B expression declined in step. Melatonin pretreatment ameliorated disturbed sleep–wake cycle, improved isoflurane-induced cognitive dysfunction, and reversed the down-regulation of CREB and NR2B expression. Our data demonstrate that sleep–wake rhythm is involved in the isoflurane-induced cognition impairment and pretreatment of melatonin has a positive effect on circadian normalization and cognition reversal. Also, NR2B–CREB signaling pathway has a critical role in this process. This study provides us a new strategy for anesthesia-induced cognitive dysfunction therapy.