title: 17β-estradiol attenuates ketamine-induced neuroapoptosis and persistent cognitive deficits in the developing brain.
abstract: Previous studies have demonstrated that the commonly used anesthetic ketamine can induce widespread neuroapoptosis in the neonatal brain and can cause persistent cognitive impairments as the animal matures. Therefore, searching for adjunctive neuroprotective strategies that inhibit ketamine-induced neuroapoptosis and persistent cognitive impairments is highly warranted. The primary goal of this study was to investigate the protective effect of 17β-estradiol against ketamine-induced neuroapoptosis and persistent cognitive impairments in adult rats. Starting from postnatal day 7, Sprague-Dawley male rat pups were given a daily administration of ketamine (75mg/kg, i.p.) or 17β-estradiol (600μg/kg, s.c.) in combination with ketamine (75mg/kg, i.p.). The animals were treated for three consecutive days. 24h after the last injection, the rats were decapitated, and the prefrontal cortex (PFC) was isolated to detect neuroapoptosis by cleaved caspase-3 immunohistochemistry and by using the TUNEL assay. The neuroactive steroid 17β-estradiol was quantified using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The protein levels of BDNF and pAkt were measured by western blot analysis. At two months of age (60 days), the learning and memory abilities were tested using the Morris water maze. The results showed that ketamine triggered significant neuroapoptosis in the neonatal PFC accompanied by the downregulation of 17β-estradiol, BDNF and pAkt. The co-administration of 17β-estradiol with ketamine attenuated these changes. Moreover, 17β-estradiol significantly reversed the learning and memory deficits observed at 60 days of age. In brief, our present data demonstrate that 17β-estradiol attenuates ketamine-induced neuroapoptosis and reverses long-term cognitive deficits in developing rats and thus may be a potential therapeutic and neuroprotective method for the treatment of neurodevelopmental disorders. This article is part of a Special Issue entitled SI: Brain and Memory.
authors.affiliation: Department of Anesthesiology, Hebei General Hospital, Shijiazhuang, Hebei province 050051, China.
authors.forename: Jianli
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Gynecology, Hebei General Hospital, Shijiazhuang, Hebei province 050051, China.
authors.forename: Bei
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, Bethune International Peace Hospital of Chinese PLA, Shijiazhuang, Hebei province 050082, China.
authors.forename: Honghai
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Pharmacy, Bethune International Peace Hospital of Chinese PLA, Shijiazhuang, Hebei province 050082, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Pharmacy, Bethune International Peace Hospital of Chinese PLA, Shijiazhuang, Hebei province 050082, China.
authors.forename: Gai
authors.initials: G
authors.lastname: Xue
authors.affiliation: Department of Pharmacy, Bethune International Peace Hospital of Chinese PLA, Shijiazhuang, Hebei province 050082, China. Electronic address: biph2011@163.com.
authors.forename: Yanning
authors.initials: Y
authors.lastname: Hou
mesh_terms: D000778:Anesthetics, Dissociative / Q000633:toxicity; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy*; D004958:Estradiol / Q000494:pharmacology*; D007649:Ketamine / Q000633:toxicity*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010766:Phosphorylation; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000254:growth & development / Q000503:physiopathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D065852:Spatial Memory / Q000187:drug effects / Q000502:physiology
chemical_list: D000778:Anesthetics, Dissociative; D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D004958:Estradiol; D007649:Ketamine; D051057:Proto-Oncogene Proteins c-akt
keywords: 17β-estradiol; BDNF; Behavioral deficits; Ketamine; Neurodegeneration; pAkt