title: Dexmedetomidine attenuates repeated propofol exposure-induced hippocampal apoptosis, PI3K/Akt/Gsk-3β signaling disruption, and juvenile cognitive deficits in neonatal rats.
abstract: Propofol is one of the most widely used intravenous anesthetics. However, repeated exposure to propofol may cause neurodegeneration in the developing brain. Dexmedetomidine (Dex), an α2 adrenoceptor agonist, has been previously demonstrated to provide neuroprotection against neuroapoptosis and neurocognitive impairments induced by several anesthetics. Thus, the current study aimed to investigate the effect of Dex on neonatal propofol-induced neuroapoptosis and juvenile spatial learning/memory deficits. Propofol (30 mg/kg) was intraperiotoneally administered to 7‑day‑old Sprague Dawley rats (n=75) three times each day at 90 min intervals for seven consecutive days with or without Dex (75 µg/kg) treatment 20 min prior to propofol injection. Following repeated propofol exposure, reduced Akt and GSK‑3β phosphorylation, increased cleaved caspase‑3 expression levels, an increased Bax/Bcl‑2 ratio, and increased terminal deoxynucleotidyl transferase‑mediated dUTP nick‑end labeling (TUNEL)‑positive cells in the CA1 hippocampal subregion were observed. Morris Water Maze testing at postnatal day 29 also demonstrated spatial learning and memory deficits following propofol treatment compared with the control group. Notably, these changes were significantly attenuated by Dex pretreatment. The results of the current study demonstrated that Dex ameliorates the neurocognitive impairment induced by repeated neonatal propofol challenge in rats, partially via its anti‑apoptotic action and normalization of the disruption to the PI3K/Akt/GSK‑3β signaling pathway. The present study provides preliminary evidence demonstrating the safety of propofol on the neonatal brain and the potential use of dexmedetomidine pretreatment in pediatric patients.
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, P.R. China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, P.R. China.
authors.forename: Changyi
authors.initials: C
authors.lastname: Wu
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, P.R. China.
authors.forename: Bin
authors.initials: B
authors.lastname: Han
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, P.R. China.
authors.forename: Fei
authors.initials: F
authors.lastname: Xu
authors.affiliation: Department of Otolaryngology, 316 Hospital of People's Liberation Army, Beijing 100093, P.R. China.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: Mao
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, P.R. China.
authors.forename: Xiangyang
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Anesthesiology, Peking University Third Hospital, Beijing 100191, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015415:Biomarkers; D001784:Blood Gas Analysis; D053148:Caspase 3 / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000188:drug therapy / Q000378:metabolism; D020927:Dexmedetomidine / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015742:Propofol / Q000008:administration & dosage / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000700:Analgesics; D015415:Biomarkers; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D020927:Dexmedetomidine; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D053148:Caspase 3; D015742:Propofol