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Location- and Subunit-Specific NMDA Receptors Determine the Developmental Sevoflurane Neurotoxicity Through ERK1/2 Signaling.
Mol Neurobiol. 2016 Jan; 53(1):216-230.MN

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+Show Affiliations

Department of Anesthesiology, Zhejiang Provincial People's Hospital, ShangTang Road 158, 310014, Hangzhou, China. Neuro-anesth@hotmail.com.Department of Anesthesiology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.Department of Anesthesiology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.Department of Anesthesiology, Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, China.Department of Anesthesiology, Zhejiang Provincial People's Hospital, ShangTang Road 158, 310014, Hangzhou, China.Department of Anesthesiology, Zhejiang Provincial People's Hospital, ShangTang Road 158, 310014, Hangzhou, China.Department of Anesthesiology, Zhejiang Provincial People's Hospital, ShangTang Road 158, 310014, Hangzhou, China.Department of Anesthesiology, Zhejiang Provincial People's Hospital, ShangTang Road 158, 310014, Hangzhou, China.Department of Anesthesiology, The First Affiliated Hospital, Zhejiang University, Hangzhou, China.Department of Neurobiology, Shanghai JiaoTong University School of Medicine, Shanghai, China.Department of Experimental Animal Center, Zhejiang University, Hangzhou, China.Department of Experimental Animal Center, Zhejiang University, Hangzhou, China.Department of Experimental Animal Center, Zhejiang University, Hangzhou, China.Department of Anesthesiology, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.Department of Anesthesiology, Zhejiang Provincial People's Hospital, ShangTang Road 158, 310014, Hangzhou, China. hushuangfei77@sina.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25421211

Citation

Wang, Wen-Yuan, et al. "Location- and Subunit-Specific NMDA Receptors Determine the Developmental Sevoflurane Neurotoxicity Through ERK1/2 Signaling." Molecular Neurobiology, vol. 53, no. 1, 2016, pp. 216-230.
Wang WY, Jia LJ, Luo Y, et al. Location- and Subunit-Specific NMDA Receptors Determine the Developmental Sevoflurane Neurotoxicity Through ERK1/2 Signaling. Mol Neurobiol. 2016;53(1):216-230.
Wang, W. Y., Jia, L. J., Luo, Y., Zhang, H. H., Cai, F., Mao, H., Xu, W. C., Fang, J. B., Peng, Z. Y., Ma, Z. W., Chen, Y. H., Zhang, J., Wei, Z., Yu, B. W., & Hu, S. F. (2016). Location- and Subunit-Specific NMDA Receptors Determine the Developmental Sevoflurane Neurotoxicity Through ERK1/2 Signaling. Molecular Neurobiology, 53(1), 216-230. https://doi.org/10.1007/s12035-014-9005-1
Wang WY, et al. Location- and Subunit-Specific NMDA Receptors Determine the Developmental Sevoflurane Neurotoxicity Through ERK1/2 Signaling. Mol Neurobiol. 2016;53(1):216-230. PubMed PMID: 25421211.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Location- and Subunit-Specific NMDA Receptors Determine the Developmental Sevoflurane Neurotoxicity Through ERK1/2 Signaling. AU - Wang,Wen-Yuan, AU - Jia,Li-Jie, AU - Luo,Yan, AU - Zhang,Hong-Hai, AU - Cai,Fang, AU - Mao,Hui, AU - Xu,Wei-Cai, AU - Fang,Jun-Biao, AU - Peng,Zhi-You, AU - Ma,Zheng-Wen, AU - Chen,Yan-Hong, AU - Zhang,Juan, AU - Wei,Zhen, AU - Yu,Bu-Wei, AU - Hu,Shuang-Fei, Y1 - 2014/11/25/ PY - 2014/09/17/received PY - 2014/11/13/accepted PY - 2014/11/26/entrez PY - 2014/11/26/pubmed PY - 2016/11/3/medline KW - Apoptosis KW - Developing brain KW - ERK1/2 MAPK signaling KW - NR2A-containing NMDA receptors KW - NR2B-containing NMDA receptors KW - Sevoflurane SP - 216 EP - 230 JF - Molecular neurobiology JO - Mol. Neurobiol. VL - 53 IS - 1 N2 - 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. SN - 1559-1182 UR - https://www.unboundmedicine.com/medline/citation/25421211/Location__and_Subunit_Specific_NMDA_Receptors_Determine_the_Developmental_Sevoflurane_Neurotoxicity_Through_ERK1/2_Signaling_ L2 - https://dx.doi.org/10.1007/s12035-014-9005-1 DB - PRIME DP - Unbound Medicine ER -