Neural Regeneration Research ›› 2020, Vol. 15 ›› Issue (1): 128-135.doi: 10.4103/1673-5374.264466

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

Huan Liu1, Xiang-Dan Gong1, Xin Zhao1, Yue Qian1, Xiao-Ping Gu1, Tian-Jiao Xia1, 2   

  1. 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
  • Online:2020-01-15 Published:2020-05-20
  • Contact: Xiao-Ping Gu, PhD,xiaopinggu@nju.edu.cn;Tian-Jiao Xia, PhD,tjxia@nju.edu.cn.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 81730033 (to XPG), 81701371 (to TJX), 81801380 (to XZ) and Natural Science Foundation of Jiangsu Province of China, No. BK20170654 (to TJX), BK20170129 (to XZ).

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Abstract:

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.

Key words: 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