N-甲基-D-天冬氨酸受体在脑中风发病机制中的作用研究进展

韩思雨,肇玉明

中国药学杂志 ›› 2017, Vol. 52 ›› Issue (17) : 1483-1487.

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中国药学杂志 ›› 2017, Vol. 52 ›› Issue (17) : 1483-1487. DOI: 10.11669/cpj.2017.17.002
综述

N-甲基-D-天冬氨酸受体在脑中风发病机制中的作用研究进展

  • 韩思雨a,肇玉明b*
作者信息 +

Function of N-Methyl-D-Aspartic Acid Receptors in Cerebral Stroke

  • HAN Si-yua, ZHAO Yu-mingb*
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文章历史 +

摘要

综合近年的文献,陈述并总结近年来N-甲基-D-天冬氨酸(N-methyl-D-aspartic acid, NMDA)受体在脑中风发病机制中的作用,以NMDA受体为靶点,介绍其结构、在缺血性脑中风损伤及神经再生中的作用,以及相关干预剂的抗中风研究进展。为药物开发提供理论基础。NMDA受体在中风病理过程中表现出双重性,其过度激活参与了兴奋性毒性的产生,损害机体;而另一方面,其又参与了缺血后神经再生的活动,有利于机体修复。 寻找调控NMDA受体的信号因子及揭示NMDA受体所调控的下游信号,使双重性中的损伤因素被抑制而保护/修复机制被激活的相关机制;开发相应药物是今后研究工作的重点。

Abstract

Cerebral stroke is caused by the interrupt of blood supply either by the blockage or by the rupture of the brain blood vessels. After the activation of the ischemic cascades, a series of neurochemical reactions might occur which involves the excess release of the excitatory amino acids. The ionotropic glutamate receptor of N-methyl-D-aspartic acid subtype (NMDA receptor) has been proven to play dual roles in the ischemic insults. On one hand, NMDA receptor has been proven to initiate the ischemic impairment, leading to the neuronal death. On the other hand, NMDA receptor is involved in the endo-neurogenesis process after the ischemic onset. Herein, we summarized the recent studies about the structures and functions of NMDA receptor in ischemic stroke pathogenesis.

关键词

脑中风 / N-甲基-D-天冬氨酸受体 / 神经损伤 / 神经再生 / 药物干预

Key words

cerebral stroke / NMDA receptor / neuronal damage / neurogenesis / drug intervention

引用本文

导出引用
韩思雨,肇玉明. N-甲基-D-天冬氨酸受体在脑中风发病机制中的作用研究进展[J]. 中国药学杂志, 2017, 52(17): 1483-1487 https://doi.org/10.11669/cpj.2017.17.002
HAN Si-yu, ZHAO Yu-ming. Function of N-Methyl-D-Aspartic Acid Receptors in Cerebral Stroke[J]. Chinese Pharmaceutical Journal, 2017, 52(17): 1483-1487 https://doi.org/10.11669/cpj.2017.17.002
中图分类号: R741   

参考文献

[1] MOZAFFARIAN D, BENJAMIN E J, GO A S, et al. Executive summary:heart disease and stroke statistics-2016 update: a report from the American Heart Association[J]. Circulation, 2016, 133(4):447-454.
[2] MARTIN L J, AL-ABDULLA N A, BRAMBRINK A M, et al. Neurodegeneration in excitotoxicity, global cerebral ischemia, and target deprivation: a perspective on the contributions of apoptosis and necrosis[J]. Brain Res Bull, 1998, 46(4):281-309.
[3] JAMES N C K, JOHN A K. Ionotropic and metabotropic glutamate receptor structure and pharmacology[J]. Psychopharmacology, 2005, 179(1):4-29.
[4] BARCOMB K, HELL J W, BENKE T A, et al. The CaMKII/GluN2B protein interaction maintains synaptic strength[J]. J Biol Chem, 2016,291(31):16082-16089.
[5] MESIC I, MADRY C, GEIDER K, et al. The N-terminal domain of the GluN3A subunit determines the efficacy of glycine-activated NMDA receptors[J]. Neuropharmacology, 2016,105: 133-141.
[6] PRYBYLOWSKI K, WENTHOLD R J. N-Methyl-D-aspartate receptor subunit assembly and trafficking to the synapse[J]. J Biol Chem, 2004, 279(11):9673-9676.
[7] LIU D D, YANG Q, LI S T. Activation of extrasynaptic NMDA receptors induces LTD in rat hippocampal CA1 neurons[J]. Brain Res Bull, 2013, 93(1):10-16.
[8] HARDINGHA M, YUKO F, HILMAR B, et al. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways[J]. Nat Neurosci, 2002, 5(5):405-414.
[9] LOZOVAYA N A, GREBENYUK S E, TSINTSADZE T S, et al. Extrasynaptic NR2B and NR2D subunits of NMDA receptors shape ‘superslow’ after burst EPSC in rat hippocampus[J]. J Physiol, 2004, 558(2):451-463.
[10] THOMAS C G, MILLER A J, WESTBROOK G L. Synaptic and extrasynaptic NMDA receptor NR2 subunits in cultured hippocampal neurons[J]. J Neurophysiol, 2006, 95(3):1727-3174.
[11] CIESIELS J, SU T P, TSAI S Y. Myristic acid hitchhiking on sigma-1 receptor to fend off neurodegeneration[J]. Receptors Clin Investig, 2016, 3(1):1-5.
[12] BAE C Y, SUN H S. TRPM7 in cerebral ischemia and potential target for drug development in stroke[J]. Acta Pharmacol Sin(中国药理学报), 2011, 32(6):725-733.
[13] LIU S B, ZHAO M G. Neuroprotective effect of estrogen: role of nonsynaptic NR2B-containing NMDA receptors[J]. Brain Res Bull, 2013, 93(1):27-31.
[14] KUCARZ K, BACH A, LAURITZEN, et al. PSD-95 uncoupling from NMDA receptors by Tat-N-dimer ameliorates neuronal depolarisation in cortical spreading depression[J]. J Cereb Blood Flow Metab, 2016,37(5):1820-1828.
[15] CAO J, SEMENOVA M M, SOLOVYAN V T, et al. Distinct requirements for p38 alpha and c-Jun N-terminal kinase stress-activated protein kinases in different forms of apoptotic neuronal death[J]. J Biol Chem, 2004, 279(34):35903-35913.
[16] ROBERT A, CROZIER C B, YU R H, et al. BDNF Modulation of NMDA receptors is activity dependent[J]. J Neurophysiol, 2008,100(6):3264-3274.
[17] STUCKY A, BAKSHI K P, FRIEDMAN E, et al. Prenatal cocaine exposure upregulates BDNF-TrkB signaling[J]. PLoS One, 2016, 11(8):e0160585.
[18] NAKAI T, NAGAI T, TANAKA M, et al. Girdin phosphorylation is crucial for synaptic plasticity and memory: a potential role in the interaction of BDNF/TrkB/Akt signaling with NMDA receptor[J]. J Neurosci, 2014, 34(45):14995-15008.
[19] MING G L, SONG H. Adult neurogenesis in the mammalian central nervous system[J]. Annu Rev Neurosci, 2005, 28(1):223-250.
[20] RUBIO-CASILLAS A, FERNNDEZ-GUASTI A. The dose makes the poison: from glutamate-mediated neurogenesis to neuronal atrophy and depression[J]. Rev Neurosci, 2016,27(16):599-622.
[21] MARIC D, LIU Q Y, GRANT G M, et al. Functional ionotropic glutamate receptors emerge during terminal cell division and early neuronal differentiation of rat neuroepithelial cells[J]. J Neurosci Res, 2000, 61(6):652-662.
[22] BERNABEU R, SHARP F R. NMDA and AMPA/kainite glutamate receptors modulate dentate neurogenesis and CA3 synapsinl in normal and ischemic hippocampus[J]. J Cereb Blood Flow Metab, 2000,20(12):1669-1680.
[23] ARVIDSSON A, KOKAIA Z, LINDVALL O. N-methyl-D-aspartate receptor-mediated increase of neurogenesis in adult rat dentate gyrus following stroke[J]. Eur J Neurosci, 2001, 14(1):10-18.
[24] QIAN C, HE S, HU X L, et al. Differential roles of NR2A- and NR2B-containing NMDA receptors in activity-dependent Brain-Derived Neurotrophic Factor gene regulation and limbic epileptogenesis[J]. J Neurosci, 2007, 27(3):542-552.
[25] FROST E E, ZHOU Z C, KRASNESKY K, et al. Initiation of oligodendrocyte progenitor cell migration by a PDGF-A activated Extracellular Regulated Kinase (ERK) Signaling pathway[J]. Neurochem Res, 2009, 34(1):169-181.
[26] LUO C X, ZHU X J, ZHOU Q G, et al. Reduced neuronal nitricoxide synthase isinvolved in ischemia-induced hippocampal neurogenesis byup-regulating inducible nitricoxide synthase expression[J]. J Neurochem, 2007, 103(5):1872-1882.
[27] LANGTON J M, KIM J H, NICHOLAS J, et al. The effect of the NMDA receptor antagonist MK-801 on the acquisition and extinction of learned fear in the developing rat[J]. Learn Mem, 2007, 14(10):665-668.
[28] ZHOU H H, TANG Y, ZHANG X Y, et al. Delayed administration of Tat-HA-NR2B9c promotes recovery after stroke in rats[J]. Stroke, 2015, 46(5):1352-1358.
[29] NUMAKAWA T, SUZUKI S, KUMAMARU E, et al. BDNF Function and intracellular signaling in neurons[J]. Histol Histopathol, 2010, 25(2):237-258.
[30] BIRK D M, BARBATO J, MUREEBE L, et al. Current insights on the biology and clinical aspects of VEGF regulation[J]. Vasc Endovascular Surg, 2009, 42(6):517-530.
[31] ZHANG Z S, ZHU Y P. NMDN Receptor select autagonist-conotoxin[J]. Chin Pharm J(中国药学杂志),2005,40(12):888-890.

基金

国家自然科学基金资助项目(31570856);北京市自然科学基金资助项目(5152005);2016年北京市教育委员会科技计划一般项目基金资助项目(KM201610025003); 首都医科大学首都医科大学本科学生科研训练项目(7NZDS2015)
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