title: Reactive Oxygen Species-mediated Loss of Phenotype of Parvalbumin Interneurons Contributes to Long-term Cognitive Impairments After Repeated Neonatal Ketamine Exposures.
abstract: Ketamine, a common anesthetic used for pediatric patients, has been shown to induce neurotoxicity and alter adolescent behaviors in rats when administered during neonatal period. However, the mechanisms underlying this kind of neurotoxicity remain largely to be determined. Herein, we studied whether the reactive oxygen species (ROS) due to the increased NOX2 mediates loss of phenotype of PV interneurons and thus contributes to long-term cognitive impairments after repeated ketamine exposures. Sprague-Dawley male rat pups received a daily administration of ketamine intraperitoneally (75 mg/kg) from postnatal day 6 (P6) to P8 for three consecutive days. For the interventional study, pups were treated with a NADPH oxidase inhibitor, apocynin (Apo). Learning and memory abilities were tested by the open field, fear conditioning, and Morris water maze on P40, P42-44, and P50-56, respectively. For histological and biochemical assays, a separate cohort of rats was killed on P9 or P60, and the brain tissues were harvested. Our results showed the upregulation of 8-OHdG and gp91/NOX2 and downregulation of PV and glutamic acid decarboxylase 67 (GAD67) after repeated ketamine exposures, which co-occurred with the long-term cognitive impairments as evidenced by the decreased freezing time to context. However, Apo treatment attenuated these abnormalities. Our results suggest that oxidative damage, probably due to the increased NOX2, mediates loss of phenotype of PV interneurons and thus contributes to long-term cognitive impairments after repeated ketamine exposures. Moreover, the inhibition of NADPH oxidase may protect against cognitive dysfunction.
authors.affiliation: Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China.
authors.forename: Xiao-Ru
authors.initials: XR
authors.lastname: Sun
authors.affiliation: Department of Anesthesiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, 210009, China.
authors.forename: Zhen-Zhen
authors.initials: ZZ
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, 22 Hankou Road, Nanjing, 210093, China.
authors.forename: Hong-Ting
authors.initials: HT
authors.lastname: Zhao
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, 22 Hankou Road, Nanjing, 210093, China.
authors.forename: Hui-Hui
authors.initials: HH
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, 210009, China.
authors.forename: Mu-Huo
authors.initials: MH
authors.lastname: Ji
authors.affiliation: Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, 22 Hankou Road, Nanjing, 210093, China. likuanyu@nju.edu.cn.
authors.forename: Kuan-Yu
authors.initials: KY
authors.lastname: Li
authors.affiliation: Department of Anesthesiology, Zhongda Hospital, School of Medicine, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, 210009, China. yjyangjj@126.com.
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Yang
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D001007:Anxiety; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D060825:Cognitive Dysfunction / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D007395:Interneurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007649:Ketamine / Q000633:toxicity*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism; D010320:Parvalbumins / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D000098:Acetophenones; D004791:Enzyme Inhibitors; D008562:Membrane Glycoproteins; D010320:Parvalbumins; D017382:Reactive Oxygen Species; D007649:Ketamine; C056165:acetovanillone; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: Cognitive impairment; Ketamine; NOX2; Parvalbumin interneuron