title: Melatonin pretreatment prevents isoflurane-induced cognitive dysfunction by modulating sleep-wake rhythm in mice.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  6h 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical Department of Nanjing University, 321 Zhong Shan Road, Nanjing, Jiangsu 210008, PR China. Electronic address: annextj@126.com.
authors.forename: Tianjiao
authors.initials: T
authors.lastname: Xia
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical Department of Nanjing University, 321 Zhong Shan Road, Nanjing, Jiangsu 210008, PR China. Electronic address: cuiyin1030@163.com.
authors.forename: Yin
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical Department of Nanjing University, 321 Zhong Shan Road, Nanjing, Jiangsu 210008, PR China. Electronic address: chuss0807@163.com.
authors.forename: Shuaishuai
authors.initials: S
authors.lastname: Chu
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical Department of Nanjing University, 321 Zhong Shan Road, Nanjing, Jiangsu 210008, PR China. Electronic address: 1030121845@qq.com.
authors.forename: Jia
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical Department of Nanjing University, 321 Zhong Shan Road, Nanjing, Jiangsu 210008, PR China. Electronic address: money890713moon@163.com.
authors.forename: Yue
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical Department of Nanjing University, 321 Zhong Shan Road, Nanjing, Jiangsu 210008, PR China. Electronic address: mazhengliang1964@nju.edu.cn.
authors.forename: Zhengliang
authors.initials: Z
authors.lastname: Ma
authors.affiliation: Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical Department of Nanjing University, 321 Zhong Shan Road, Nanjing, Jiangsu 210008, PR China. Electronic address: 13813996903@126.com.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Gu
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D007530:Isoflurane / Q000633:toxicity*; D008297:Male; D008550:Melatonin / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D012893:Sleep Wake Disorders / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism*; D065852:Spatial Memory / Q000187:drug effects*
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D007530:Isoflurane; D008550:Melatonin
keywords: CREB; Cognitive; Isoflurane; Melatonin; NR2B; Sleep–wake rhythm