多奈哌齐抑制钠通道和N-甲基-D-天冬氨酸受体通道保护神经元的机制

郭婷婷,王伟平,王晓良

中国药学杂志 ›› 2017, Vol. 52 ›› Issue (24) : 2166-2171.

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中国药学杂志 ›› 2017, Vol. 52 ›› Issue (24) : 2166-2171. DOI: 10.11669/cpj.2017.24.007
论著

多奈哌齐抑制钠通道和N-甲基-D-天冬氨酸受体通道保护神经元的机制

  • 郭婷婷,王伟平,王晓良*
作者信息 +

Mechanism of Donepezil Protecting Neurons by Inhibiting Sodium Channel and NMDA Receptor Channel

  • GUO Ting-ting, WANG Wei-ping, WANG Xiao-liang*
Author information +
文章历史 +

摘要

目的 研究多奈哌齐(donepezil)对谷氨酸诱导的神经元损伤的保护作用与对钠电流和N-甲基-D-天冬氨酸(N-methyl-D-aspartate,NMDA)受体介导电流的影响。方法 原代培养出生12 h的Wistar乳鼠皮层和海马神经元,分别取8~12 d的皮层和海马神经元,应用四甲基偶氮唑蓝(MTT)法观察多奈哌齐对谷氨酸损伤神经元的保护作用,以选择性Na+通道阻断剂河豚毒素(TTX)和选择性NMDA受体阻断剂地佐环平(MK-801)为阳性药;应用手动膜片钳,观察多奈哌齐对海马和皮层神经元Na+电流以及NMDA受体介导电流的影响。结果 多奈哌齐和MK-801对谷氨酸诱导的神经元损伤均具有保护作用,TTX可一定程度上增强MK-801的保护作用;电生理研究发现,1 μmol·L-1多奈哌齐对海马以及皮层神经元Na+电流和NMDA受体介导的电流均有轻微的抑制作用,10 μmol·L-1多奈哌齐对海马以及皮层神经元Na+电流和NMDA受体介导的电流均有明显的抑制作用。结论 多奈哌齐对谷氨酸损伤的神经元具有保护作用,其作用机制可能与其抑制Na+通道和NMDA受体通道电流有关。

Abstract

OBJECTIVE To study the protective effect of donepezil on L-glutamic acid-induced injury and the effects on Na+ currents and NMDA receptor-mediated currents in neurons. METHODS Cortical and hippocampal neurons were isolated from postnatal 12 h Wistar rats and were cultured for 8-12 d. The protective effect of donepezil on L-glutamic acid-induced injury in neurons was investigated by MTT cell viability assay, and selective Na+ channel blocker TTX and selective NMDA receptor blocker MK-801 were taken as positive drugs. The effects of donepezil on Na+ and NMDA receptor-mediated current in hippocampal and cortical neurons was studied by using manual patch clamp. RESULTS Donepezil and MK-801 showed protective effects on L-glutamic acid-induced injury model, and TTX can slightly enhance the protective effect of MK-801. 1 μmol·L-1 donepezil slightly inhibited Na+ currents and NMDA receptor-mediated currents of hippocampal and cortical neurons and 10 μmol·L-1 donepezil showed obviously inhibiting effects on Na+ currents and NMDA receptor-mediated currents of hippocampal and cortical neurons. CONCLUSION Donepezil can protect neurons from glutamic acid damage, and its mechanism is related to inhibiting current of Na+ channel and NMDA receptor channel.

关键词

多奈哌齐 / 谷氨酸 / 钠通道 / N-甲基-D-天冬氨酸受体 / 神经保护

Key words

donepezil / L-glutamic acid / sodium channel / NMDA receptor / neuroprotection

引用本文

导出引用
郭婷婷,王伟平,王晓良. 多奈哌齐抑制钠通道和N-甲基-D-天冬氨酸受体通道保护神经元的机制[J]. 中国药学杂志, 2017, 52(24): 2166-2171 https://doi.org/10.11669/cpj.2017.24.007
GUO Ting-ting, WANG Wei-ping, WANG Xiao-liang. Mechanism of Donepezil Protecting Neurons by Inhibiting Sodium Channel and NMDA Receptor Channel[J]. Chinese Pharmaceutical Journal, 2017, 52(24): 2166-2171 https://doi.org/10.11669/cpj.2017.24.007
中图分类号: R965   

参考文献

[1] BRASSAI A, SUVANJEIEV R G, BAN E G, et al. Role of synaptic and nonsynaptic glutamate receptors in ischaemia induced neurotoxicity[J]. Brain Res Bull, 2015, 112(2015):1-6.
[2] ZHOU Q, SHENG M. NMDA Receptors in nervous system diseases[J]. Neuropharmacology, 2013, 74(2013):69-75.
[3] LEWERENZ J, MAHER P. Chronic glutamate toxicity in neurodegenerative diseases-what is the evidence?[J]. Front Neurosci, 2015, 9:469.
[4] HYND M R, SCOTT H L, DODD P R. Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer′s disease[J]. Neurochem Int, 2004, 45(5):583-595.
[5] KIHARA T, SHIMOHAMA S, SAWADA H, et al. Protective effect of dopamine D2 agonists in cortical neurons via the phosphatidylinositol 3 kinase cascade[J]. J Neurosci Res, 2002, 70(3):274-282.
[6] REVETT T J, BAKER G B, JHAMANDAS J, et al. Glutamate system, amyloid ss peptides and tau protein:functional interrelationships and relevance to Alzheimer disease pathology[J]. J Psychiatry Neurosci, 2013, 38(1):6-23.
[7] ZADORI D, VERES G, SZALARDY L, et al. Glutamatergic dysfunctioning in Alzheimer's disease and related therapeutic targets[J]. J Alzheimers Dis, 2014, 42(suppl 3):177-187.
[8] HENCHCLIFFE C, BEAL M F. Excitotoxicity[J]. Handb Clin Neurol, 2007, 83:553-569.
[9] BONFOCO E, KRAINC D, ANKARCRONA M, et al. Apoptosis and necrosis:two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures[J]. Proc Natl Acad Sci USA, 1995, 92(16):7162-7166.
[10] YAMAGISHI R,AIHARA M. Neuroprotective effect of astaxanthin against rat retinal ganglion cell death under various stresses that induce apoptosis and necrosis[J]. Mol Vis, 2014, 20:1796-1805.
[11] CHOI D W. Ionic dependence of glutamate neurotoxicity[J]. J Neurosci, 1987, 7(2):369-379.
[12] HYND M R, SCOTT H L, DODD P R. Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer′s disease[J]. Neurochem Int, 2004, 45(5):583-595.
[13] YE H, JALINI S, ZHANG L, et al. Early ischemia enhances action potential-dependent, spontaneous glutamatergic responses in CA1 neurons[J]. J Cereb Blood Flow Metab, 2010, 30(3):555-565.
[14] JELIC V,DARREH-SHORI T. Donepezil:a review of pharmacological characteristics and role in the management of Alzheimer disease[J]. Clin Med Insights Ther, 2010, 2:771-778.
[15] ROY R, NICCOLINI F, PAGANO G, et al. Cholinergic imaging in dementia spectrum disorders[J]. Eur J Nucl Med Mol Imaging, 2016, 43(7):1376-1386.
[16] GELDENHUYS W J,DARVESH A S. Pharmacotherapy of Alzheimer's disease:current and future trends[J]. Expert Rev Neurother, 2015, 15(1):3-5.
[17] TAKADA Y, YONEZAWA A, KUME T, et al. Nicotinic acetylcholine receptor-mediated neuroprotection by donepezil against glutamate neurotoxicity in rat cortical neurons[J]. J Pharmacol Exp Ther, 2003, 306(2):772-777.
[18] TAKADA-TAKATORI Y, KUME T, SUGIMOTO M, et al. Acetylcholinesterase inhibitors used in treatment of Alzheimer's disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade[J]. Neuropharmacology, 2006, 51(3):474-486.
[19] SHEN H, KIHARA T, HONGO H, et al. Neuroprotection by donepezil against glutamate excitotoxicity involves stimulation of alpha7 nicotinic receptors and internalization of NMDA receptors[J]. Br J Pharmacol, 2010, 161(1):127-139.
[20] AKAIKE A. Preclinical evidence of neuroprotection by cholinesterase inhibitors[J]. Alzheimer Dis Assoc Disord, 2006, 20(2 suppl 1):8-11.
[21] YU B,HU G Y. Donepezil blocks voltage-gated ion channels in rat dissociated hippocampal neurons[J]. Eur J Pharmacol, 2005, 508(1-3):15-21.

基金

国家科技部“重大新药创制”科技重大专项资助(2012ZX09301002-004);重大协同创新项目-重大前沿研究资助(2016-I2M-1-010)
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