GLYX-13 pretreatment ameliorates long-term isoflurane exposure-induced cognitive impairment in mice  

作　　者：Huan Liu Xiang-Dan Gong Xin Zhao Yue Qian Xiao-Ping Gu Tian-Jiao Xia 

机构地区：[1]Department of Anesthesiology,The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School,Nanjing,Jiangsu Province,China [2]Jiangsu Key Laboratory of Molecular Medicine,Medical School of Nanjing University,Nanjing,Jiangsu Province,China

出　　处：《Neural Regeneration Research》2020年第1期128-135,共8页中国神经再生研究（英文版）

基　　金：supported by the National Natural Science Foundation of China,No.81730033(to XPG),81701371(to TJX),81801380(to XZ);Natural Science Foundation of Jiangsu Province of China,No.BK20170654(to TJX),BK20170129(to XZ)

摘　　要：Accumulating evidence indicates that inhalation anesthetics induce or increase the risk of cognitive impairment. GLYX-13（rapastinel） acts on the glycine site of N-methyl-D-aspartate receptors（NMDARs） and has been shown to enhance hippocampus-dependent learning and memory function. However, the mechanisms by which GLYX-13 affects learning and memory function are still unclear. In this study, we investigated these mechanisms in a mouse model of long-term anesthesia exposure. Mice were intravenously administered 1 mg/kg GLYX-13 at 2 hours before isoflurane exposure（1.5% for 6 hours）. Cognitive function was assessed using the contextual fear conditioning test and the novel object recognition test. The mRNA expression and phosphorylated protein levels of NMDAR pathway components, N-methyl-D-aspartate receptor subunit 2B（NR2B）-Ca2+/calmodulin dependent protein kinase II（CaMKII）-cyclic adenosine monophosphate response element binding protein（CREB）, in the hippocampus were evaluated by quantitative RT-PCR and western blot assay. Pretreatment with GLYX-13 ameliorated isoflurane exposure-induced cognitive impairment and restored NR2B, CaMKII and CREB mRNA and phosphorylated protein levels. Intracerebroventricular injection of KN93, a selective CaMKII inhibitor, significantly diminished the effect of GLYX-13 on cognitive function and NR2B, CaMKII and CREB levels in the hippocampus. Taken together, our findings suggest that GLYX-13 pretreatment alleviates isoflurane-induced cognitive dysfunction by protecting against perturbation of the NR2B/CaMKII/CREB signaling pathway in the hippocampus. Therefore, GLYX-13 may have therapeutic potential for the treatment of anesthesia-induced cognitive dysfunction. This study was approved by the Experimental Animal Ethics Committee of Drum Tower Hospital affiliated to the Medical College of Nanjing University, China（approval No. 20171102） on November 20, 2017.Accumulating evidence indicates that inhalation anesthetics induce or increase the risk of cognitive impairment.GLYX-13(rapastinel)acts on the glycine site of N-methyl-D-aspartate receptors(NMDARs)and has been shown to enhance hippocampus-dependent learning and memory function.However,the mechanisms by which GLYX-13 affects learning and memory function are still unclear.In this study,we investigated these mechanisms in a mouse model of long-term anesthesia exposure.Mice were intravenously administered 1 mg/kg GLYX-13 at 2 hours before isoflurane exposure(1.5%for 6 hours).Cognitive function was assessed using the contextual fear conditioning test and the novel object recognition test.The mRNA expression and phosphorylated protein levels of NMDAR pathway components,N-methyl-D-aspartate receptor subunit 2B(NR2B)-Ca^2+/calmodulin dependent protein kinaseⅡ(CaMKII)-cyclic adenosine monophosphate response element binding protein(CREB),in the hippocampus were evaluated by quantitative RT-PCR and western blot assay.Pretreatment with GLYX-13 ameliorated isoflurane exposure-induced cognitive impairment and restored NR2B,CaMKII and CREB mRNA and phosphorylated protein levels.Intracerebroventricular injection of KN93,a selective CaMKII inhibitor,significantly diminished the effect of GLYX-13 on cognitive function and NR2B,CaMKII and CREB levels in the hippocampus.Taken together,our findings suggest that GLYX-13 pretreatment alleviates isoflurane-induced cognitive dysfunction by protecting against perturbation of the NR2B/CaMKII/CREB signaling pathway in the hippocampus.Therefore,GLYX-13 may have therapeutic potential for the treatment of anesthesia-induced cognitive dysfunction.This study was approved by the Experimental Animal Ethics Committee of Drum Tower Hospital affiliated to the Medical College of Nanjing University,China(approval No.20171102)on November 20,2017.

关 键 词：Ca2+/calmodulin-dependent protein kinase II cognitive impairment contextual fear conditioning cyclic adenosine monophosphate response element binding protein GLYX-13 ISOFLURANE N-methyl-D-aspartate receptor novel object recognition rapastinel 

分 类 号：R453[医药卫生—治疗学] R842.1[医药卫生—临床医学]