title: Location- and Subunit-Specific NMDA Receptors Determine the Developmental Sevoflurane Neurotoxicity Through ERK1/2 Signaling.
abstract: It is well established that developmental exposure of sevoflurane (an inhalational anesthetic) is capable of inducing neuronal apoptosis and subsequent learning and memory disorders. Synaptic NMDA receptors activity plays an essential role in cell survival, while the extra-synaptic NMDA receptors activation is usually associated with cell death. However, whether synaptic or extra-synaptic NMDA receptors mediate developmental sevoflurane neurotoxicity is largely unknown. Here, we show that developmental sevoflurane treatment decreased NR2A, but increased NR2B subunit expression both in vitro and in vivo. Sevoflurane-induced neuronal apoptosis was attenuated by synaptic NMDA receptors activation or low dose of exogenous NMDA in vitro. Interestingly, these effects could be abolished by NR2A inhibitor PEAQX, but not NR2B inhibitor Ifenprodil in vitro. In contrast, activation of extra-synaptic NMDA receptors alone had no effects on sevoflurane neurotoxicity. In the scenario of extra-synaptic NMDA receptors stimulation, however, sevoflurane-induced neuronal apoptosis could be prevented by addition of Ifenprodil, but not by PEAQX in vitro. In addition, sevoflurane neurotoxicity could also be rescued by memantine, an uncompetitive antagonist for preferential blockade of extra-synaptic NMDA receptors both in vitro and in vivo. Furthermore, we found that developmental sevoflurane-induced phospho-ERK1/2 inhibition was restored by synaptic NMDA receptor activation (in vitro), low dose of NMDA (in vitro) or memantine (in vivo). And the neuroprotective role of synaptic NMDA activity was able to be reversed by MEK1/2 inhibitor U0126 in vitro. Finally, administration of memantine or NMDA significantly improved spatial learning and memory dysfunctions induced by developmental sevoflurane exposure without influence on locomotor activity. These results indicated that activation of synaptic NR2A-containing NMDA receptors, or inhibition of extra-synaptic NR2B-containing NMDA receptors contributed to the relief of sevoflurane neurotoxicity, and the ERK1/2 MAPK signaling may be involved in this process.
authors.affiliation: Department of Anesthesiology, Zhejiang Provincial People's Hospital, ShangTang Road 158, 310014, Hangzhou, China. Neuro-anesth@hotmail.com.
authors.forename: Wen-Yuan
authors.initials: WY
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
authors.forename: Li-Jie
authors.initials: LJ
authors.lastname: Jia
authors.affiliation: Department of Anesthesiology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Anesthesiology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, China.
authors.forename: Hong-Hai
authors.initials: HH
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Zhejiang Provincial People's Hospital, ShangTang Road 158, 310014, Hangzhou, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Cai
authors.affiliation: Department of Anesthesiology, Zhejiang Provincial People's Hospital, ShangTang Road 158, 310014, Hangzhou, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Mao
authors.affiliation: Department of Anesthesiology, Zhejiang Provincial People's Hospital, ShangTang Road 158, 310014, Hangzhou, China.
authors.forename: Wei-Cai
authors.initials: WC
authors.lastname: Xu
authors.affiliation: Department of Anesthesiology, Zhejiang Provincial People's Hospital, ShangTang Road 158, 310014, Hangzhou, China.
authors.forename: Jun-Biao
authors.initials: JB
authors.lastname: Fang
authors.affiliation: Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.
authors.forename: Zhi-You
authors.initials: ZY
authors.lastname: Peng
authors.affiliation: Department of Neurobiology, Shanghai JiaoTong University School of Medicine, Shanghai, China.
authors.forename: Zheng-Wen
authors.initials: ZW
authors.lastname: Ma
authors.affiliation: Department of Experimental Animal Center, Zhejiang University, Hangzhou, China.
authors.forename: Yan-Hong
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Experimental Animal Center, Zhejiang University, Hangzhou, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Experimental Animal Center, Zhejiang University, Hangzhou, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wei
authors.affiliation: Department of Anesthesiology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
authors.forename: Bu-Wei
authors.initials: BW
authors.lastname: Yu
authors.affiliation: Department of Anesthesiology, Zhejiang Provincial People's Hospital, ShangTang Road 158, 310014, Hangzhou, China. hushuangfei77@sina.com.
authors.forename: Shuang-Fei
authors.initials: SF
authors.lastname: Hu
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008738:Methyl Ethers / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000188:drug therapy; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D000077149:Sevoflurane; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology
chemical_list: D018691:Excitatory Amino Acid Antagonists; D008738:Methyl Ethers; D016194:Receptors, N-Methyl-D-Aspartate; D000077149:Sevoflurane
keywords: Apoptosis; Developing brain; ERK1/2 MAPK signaling; NR2A-containing NMDA receptors; NR2B-containing NMDA receptors; Sevoflurane