title: Repeated administration of ketamine can induce hippocampal neurodegeneration and long-term cognitive impairment via the ROS/HIF-1α pathway in developing rats.
abstract: BACKGROUND
  Recent animal experiments have suggested that ketamine administration during development might induce widespread neurodegeneration and long-term cognitive deficits. The underlying mechanism is not fully understood.
  
  
  METHODS
  Immature rat hippocampal neurons and newborn rats underwent repeated exposure to ketamine, ketamine+inhibitor of hypoxia-inducible factor (HIF)-1α(YC-1), ketamine+inhibitor of reactive oxygen species(ROS) (L-carnitine) or ketamine+Ca(2+) blocker(nimodipine). Apoptosis of the hippocampal neurons was analyzed by TUNEL and flow cytometry. Intracellular ROS were measured using 2',7'-dichlorofluorescein diacetate. The expression of HIF- 1α and apoptosis-related proteins was analyzed by western blot or qPCR. As these rats grew, behavioral tests were performed to evaluate cognitive function.
  
  
  RESULTS
  The apoptotic rate in the ketamine group was significantly higher than that in the other groups, and the intracellular ROS levels in the ketamine and ketamine+YC-1 groups were higher than those in the other groups. The expression of HIF- 1α, p53, BNIP3 and cleaved caspase-3 proteins increased, and the ratio of Bcl-2/Bax decreased in the ketamine group. The transcriptional levels of HIF-1α in the ketamine and ketamine+YC-1 groups were higher than those in the other groups. Cognitive deficits were found only in the ketamine group.
  
  
  CONCLUSIONS
  We suggest that ketamine-induced neurodegeneration in neonatal rats, followed by long-term cognitive deficits, might be mediated via the ROS/HIF-1α pathway.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai 200011, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Yan
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002331:Carnitine / Q000494:pharmacology; D002478:Cells, Cultured; D003072:Cognition Disorders / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007191:Indazoles / Q000494:pharmacology; D007649:Ketamine / Q000008:administration & dosage / Q000633:toxicity*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009553:Nimodipine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014803:Vitamin B Complex / Q000494:pharmacology
chemical_list: D000700:Analgesics; D002121:Calcium Channel Blockers; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007191:Indazoles; D017382:Reactive Oxygen Species; D014803:Vitamin B Complex; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D009553:Nimodipine; D007649:Ketamine; D002331:Carnitine