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Esketamine Improves Working Memory Impairment in Neuropathic Mice Through Hippocampal BDNF-TrkB Pathway
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摘要: 目的 探究艾司氯胺酮改善神经病理性疼痛所致小鼠工作记忆障碍的作用及可能机制。 方法 将2月龄雄性C57BL/6J小鼠随机均分为5组：假手术+生理盐水组（SN组）、慢性坐骨神经压迫（chronic constriction injury，CCI）+生理盐水组（CN组）、CCI+艾司氯胺酮组（CE组）、CCI+ANA-12组（CA组）、CCI+ANA-12+艾司氯胺酮组（CAE）组，每组10只。采用CCI建立神经病理性疼痛模型，于造模后第16天，CE组、CAE组分别给予艾司氯胺酮（10 mg/kg），其中CAE组于艾司氯胺酮注射前半小时给予ANA-12（0.5 mg/kg）； CA组仅给予ANA-12； SN组、CN组仅给予等量生理盐水，连续5 d腹腔注射给药。于造模后第21天开始行旷场实验、Y迷宫实验，检测小鼠机械缩足反应阈值（paw withdrawal threshold，PWT）及热缩足潜伏期（paw withdrawal latency，PWL），并于造模后第21～23天腹腔注射溴脱氧尿嘧啶核苷（Bromo-2-deoxyUridine，BrdU）。通过蛋白质免疫印迹实验检测小鼠海马脑源性神经营养因子（brain-derived neurotrophic factor，BDNF）蛋白表达，采用免疫荧光检测海马齿状回BrdU及双皮质素（doublecortin，DCX）共染阳性（BrdU+/DCX+）细胞数量。 结果 与SN组相比，CN组、CE组、CA组、CAE组PWT明显降低（P均＜0.05），PWL明显缩短（P均＜0.05）；在旷场实验中，5组小鼠的运动总距离无明显差异（P=0.142）； Y迷宫实验中，与SN组相比，CN组自发性交替正确率明显降低（P<0.001），与CN组相比，CE组自发性交替正确率明显升高（P<0.001），与CE组相比，CAE组自发性交替正确率明显降低（P=0.004）；与SN组相比，CN组BDNF表达下调（P=0.021），与CN组相比，CE组BDNF表达上调（P=0.030），与CE组相比，CAE组表达下调（P=0.043）；与SN组相比，CN组BrdU+/DCX+细胞数量明显降低（P=0.025），与CN组相比，CE组BrdU+/DCX+细胞数量明显升高（P=0.003），与CE组相比，CAE组BrdU+/DCX+细胞数量明显降低（P=0.014）。 结论 艾司氯胺酮可能通过海马BDNF-TrkB神经通路促进海马齿状回神经再生进而改善神经病理性疼痛所致的工作记忆障碍。Abstract: Objective To explore the effect of esketamine on working memory impairment in neuropathic mice and its underlying mechanism. Methods Fifty clean grade male C57BL/6J mice (2 months) were divided into 5 groups by random number table method: sham + saline (SN group), CCI + saline (CN group), CCI+(S)-ketamine(CE group), CCI + ANA-12 (CA group), CCI + ANA-12+(S)-ketamine (CAE group), with 10 mice in each group. Chronic constriction injury (CCI) was employed to establish a neuropathic pain model. On the 16th day after modeling, CE group and CAE group were administered ketamine (10 mg/kg), CAE group received ANA-12 (0.5 mg/kg) half an hour before ketamine injection, CA group was only given ANA-12, and SN group and CN group received an equivalent volume of saline. The administration was done through intraperitoneal injection for 5 consecutive days. The open-field test (OFT), paw withdrawal threshold (PWT), paw withdrawal latency (PWL) and Y-maze test were performed from day 21 after surgery. Bromo-2- deoxyUridine (BrdU) was dissolved in saline and intraperitoneally injected into the mice on days 21 to 23 after the surgery. Western blot was performed to determine the expression of Brain-derived neurotrophic factor(BDNF) in hippocampus, the immunofluorescence was performed to determine the number of bromodeoxyuridine nucleoside (BrdU) and doublecortxin (DCX) positive cells in the dentate gyrus (DG) area of hippocampal. Results Compared with SN group， the other four groups showed significant reductions in both PWT and PWL on day 21 after surgery (all P＜0.05); There was no significant difference in the total distance travelled by the 5 groups of mice (P=0.142) ; In the Y maze test, compared to SN group, the accurate percentage of spontaneous alternation in CN group showed significant reductions (P＜0.001), which was reversed by esketamine administration (P＜0.001); compared with CE group, there was a significant reduction of the accurate percentage of spontaneous alternation in CAE group (P=0.004). The expression of BDNF protein in CN group was lower than that in SN group(P=0.021) and CE group (P=0.03), and compared with CE group, the expression of BDNF was significant decreased in CEA group (P=0.043). The number of BrdU positive and DCX positive cells significantly reduced in the DG area of the hippocampus in CN group compared to SN group(P=0.025) and CE group (P=0.003). The number of BrdU positive and DCX positive cells in CAE group significantly reduced in the DG region of the hippocampus compared to CE group(P=0.014). Conclusion Esketamine improves working memory impairment in neuropathic mice and the neurogenesis in dentate gyrus area of hippocampal through the BDNF-TrkB pathway.
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Keywords:
- Esketamine /
- neuropathic pain /
- working memory /
- hippocampus
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