title: Ketamine potentiates hippocampal neurodegeneration and persistent learning and memory impairment through the PKCγ-ERK signaling pathway in the developing brain.
abstract: Ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, is widely used as a general pediatric anesthetic. Recent studies suggest that ketamine enhances neuronal apoptosis in developing rodents and nonhuman primates. The main goal of this study is to determine whether ketamine causes hippocampal neurodegeneration and behavioral deficits in adulthood, and if so, whether the effects of ketamine are associated with protein kinase C-gamma (PKCγ), extracellular signal regulated kinase (ERK)1/2 and Bcl-2 expression. Starting from postnatal day 7, Sprague-Dawley rat pups randomly received daily ketamine treatment (25, 50 and 75mg/kg, ip) for three consecutive days. Twenty-four hours after the last treatment with ketamine, the rats were decapitated, and the hippocampi were isolated for detection of neuronal apoptosis by TUNEL. The protein expression levels of PKCγ, ERK1/2 and Bcl-2 in the hippocampi were measured by western blot analysis. At 2months of age, learning and memory abilities were tested by the Morris water maze. Ketamine increased the number of apoptotic cells in the CA1 region and dentate gyrus at a dose of 75mg/kg but not at lower doses of 25 and 50mg/kg. The dose of 75mg/kg of ketamine suppressed p-PKCγ, p-ERK1/2 and Bcl-2 expression but not t-PKCγ or t-ERK expression. Ketamine administered to the developing brains of P7 rats at a dose of 75mg/kg caused learning and memory impairments in adulthood. Therefore, these data demonstrate that ketamine at a dose of 75mg/kg in the developing brain results in hippocampal neurodegeneration and persistent learning and memory impairment, which is associated with the PKCγ-ERK signaling pathway. This article is part of a Special Issue entitled: Brain Integration.
authors.affiliation: Department of Anesthesiology, The Second Hospital of Hebei Medical University, Hebei Province, Shijiazhuang 050000, China.
authors.forename: Lining
authors.initials: L
authors.lastname: Huang
authors.forename: Ya
authors.initials: Y
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Jin
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Ji
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000700:Analgesics / Q000633:toxicity*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D020287:In Situ Nick-End Labeling; D007649:Ketamine / Q000633:toxicity*; D007859:Learning Disabilities / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D018782:Maze Learning / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000700:Analgesics; D004791:Enzyme Inhibitors; D007649:Ketamine; D011493:Protein Kinase C