TREK-1阻滞剂SID1900对CUMS小鼠突触发生的调节作用-东南大学学报医学版

TREK-1阻滞剂SID1900对CUMS小鼠突触发生的调节作用

单位：1. 东南大学医学院, 江苏南京 210009;
2. 东南大学附属中大医院神经内科, 江苏南京 210009

分类号：R-332;R338.26

出版年·卷·期（页码）：2017·36·第四期（513-518）

摘要：

目的：探讨钾离子通道（TREK-1）阻滞剂SID1900对海马区域突触发生的调节作用及其可能的抗抑郁作用分子机制。方法：选用8~10周龄C57BL/6J雄性小鼠进行慢性不可预知温和应激（CUMS）造模，造模成功后给予TREK-1阻滞剂Spadin、SID1900连续28 d腹腔注射，分别于给药0、7、14、21、28 d对小鼠进行行为学测试，通过Western blotting方法检测突触相关蛋白PSD95、Synapsin 1表达水平变化。结果：CUMS小鼠蔗糖水消耗百分比较对照组显著降低，强迫游泳中不动时间显著升高，出现抑郁样表型；给药3周后，Spadin、SID1900可以使CUMS小鼠蔗糖水消耗百分比升高，但较对照组仍然降低，对开场、强迫游泳实验结果无显著影响；给药4周后，Spadin、SID1900使CUMS小鼠蔗糖水消耗百分比升高，且与对照组无差异，在强迫游泳、悬尾实验中的不动时间缩短；Western blotting检测显示，给药4周后CUMS小鼠突触相关蛋白PSD95、Synapsin 1表达升高。结论：TREK-1阻滞剂SID1900可改善抑郁症状，使突触相关蛋白PSD95、Synapsin 1表达升高，影响突触发生可能是其抗抑郁作用机制之一。

Objective:To investigate the regulatory effects of TWIK-related K⁺ channel(TREK-1) blocker SID1900 on synaptogenesis in hippocampus in order to explore the anti-depression mechanism. Methods:Adult male C57BL/6J mice of 8 to 10 weeks were chosen to set up chronic mild unpredictable stress-induced anhedonia model of depression, and TREK-1 blocker of Spadin and SID1900 was injected for 28 days, and antidepressant response of TREK-1 blocker was evaluated on chronic unpredictable mild stress model by sucrose preference test, tail suspension test, force swimming test, open field test. On dosing 0, 7, 14, 21, 28 days. We extracted the post-synaptic density protein of PSD95 and synapsin1 in hippocampus on days of 28, then detected protein level of two markers synaptogenesis protein with Western blotting. Results:The chronic mild unpredictable stress significantly decreased the sucrose preference of model mice, and the time of immobility in FST was significantly increased compared with the control mice,the CUMS mice expressed specific endophenotype of depression. Chronic treatement with Spadin or SID1900 significantly increased the sucrose preference at the end of three-week treatment compared with the CUMS mice, but still decreased compared with the control mice, and the chronic three-week treatment did no affect force swimming test and Open-field test. Chronic treatement with Spadin or SID1900 significantly increased the sucrose preference at the end of four-week treatment compared with the CUMS mice, but there was no difference compared with the control mice. The immobility time in force swimming test and tail suspension test significantly decreased compare with the CUMS mice. Chronic treatement with Spadin or SID1900 for four weeks also increased protein level of two markers of synaptogenesis, the PSD95 and synapsin1 in the hippocampus. Conclusion:TREK-1 blocker (SID1900) can improve depressive symptoms and increase the expressions of synapse associated proteins PSD95 and Synapsin 1, which maybe the antidepression mechanism of TREK-1 blocker.

参考文献：

[1] CARACI F,COPANI A,NICOLETTI F,et al.Depression and Alzheimer's disease:neurobiological links and common pharmacological targets[J].Eur J Pharmacol,2010,626(1):64-71.
[2] HAENISCH B,BONISCH H.Depression and antidepressants:Insights from knockout of dopamine,serotonin or noradrenaline re-uptake transporters[J].Pharmacol Ther,2011,129(3):352-368.
[3] HEURTEAUX C,LUCAS G,GUY N,et al.Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype[J].Nat Neurosci,2006,9(9):1134-1141.
[4] MAZELLA J,PETRAULT O,LUCAS G,et al.Spadin,a sortilin-derived peptide,targeting rodent TREK-1 channels:a new concept in the antidepressant drug design[J].PLoS Biol,2010,8(4):e1000355.
[5] DEVADER C,KHAYACHI A,VEYSSIERE J,et al.In vitro and in vivo regulation of synaptogenesis by the novel antidepressant spadin[J].Br J Pharmacol,2015,172(10):2604-2617.
[6] YE D Q,LI Y,ZHANG X R,et al.TREK1 channel blockade induces an antidepressant-like response synergizing with 5-HT1A receptor signaling[J].Eur Neuropsychopharmacol,2015,25(12):2426-2436.
[7] The National Institutes of Health Guide.The Care and Use of Laboratory Animals[S].1988.
[8] LI Y F,CHEN H X,LIU Y Q,et al.Agmatine increases proliferation of cultured hippocampal progenitor cells and hippocampal neurogenesis in chronically stressed mice[J].Acta Pharmacol Sin,2006,27(11):1395-1400.
[9] MOHAOUMAATI H,VEYSSIERE J,LABBAL F,et al.Spadin as a new antidepressant:absence of TREK-1-related side effects[J].Neuropharmacology,2012,62(1):278-288.
[10] WANG S H,ZHANG Z J,GUO Y J,et al.Hippocampal neurogenesis and behavioural studies on adult ischemic rat response to chronic mild stress[J].Behav Brain Res,2008,189(1):9-16.
[11] STERU L,CHERMAT R,THIERRY B,et al.The tail suspension test:a new method for screening antidepressants in mice[J].Psychopharmacology (Berl),1985,85(3):367-370.
[12] NEISV B,MANOSSO L M,MORETTI M,et al.Depressive-like behavior induced by tumor necrosis factor-alpha is abolished by agmatine administration[J].Behav Brain Res,2014,261(3):336-344.
[13] NEIS V B,MORETTI M,BETTIO L E,et al.Agmatine produces antidepressant-like effects by activating AMPA receptors and mTOR signaling[J].Eur Neuropsychopharmacol,2016,26(6):959-971.
[14] HART P C,BERGNER C L,SMOLINSKY A N,et al.Experimental models of anxiety for drug discovery and brain research[J].Methods Mol Biol,2010,602(11):299-321.
[15] 江开达.精神病学[M].北京:人民卫生出版社,2009:390-391.
[16] KUPFER D J,FRANK E,PHILLIPS M L,et al.Major depressive disorder:new clinical,neurobiological,and treatment perspectives[J].Lancet,2012,379(9820):1045-1055.
[17] DUMAN R S,AGHAJANIAN G K.Synaptic dysfunction in depression:potential therapeutic targets[J].Science,2012,338(6103):68-72.
[18] HERVIEU G J,CLUDERAY J E,GRAYC W,et al.Distribution and expression of TREK-1,a two-pore-domain potassium channel in the adult rat CNS[J].Neuroscience,2001,103(4):899-919.
[19] BEAUDOIN-GOBERT M,SGAMBATO-FAURE V.Serotonergic pharmacology in animal models:from behavioral disorders to dyskinesia[J].Neuropharmacology,2014,81(6):15-30.
[20] GRONLI J,MURISON R,BJORVATN B,et a1.Chroniee mild stress affects sucrose intake and sleep in rats[J].Behav Brain Res,2004,150(1-2):139-147.

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