缺血再灌注中酸敏感离子通道引起神经元损伤机制及葛根素保护作用的研究
|
摘要
缺血性脑卒中是一类具有高死亡率和高致残率的脑血管疾病,其主要病理变化是缺血性神经元损伤。许多继发因素在缺血后的脑损伤中发挥重要作用。酸中毒(acidosis)是脑缺血再灌注过程中的常见现象。脑缺血时,由于乳酸堆积和ATP水解产生H+,导致组织酸化,这种情况可以一直延续至再灌注4小时甚至更长时间,高血糖状态下细胞外pH可以降低至6.0。胞外酸化直接激活了酸敏感离子通道(acid-sensing ion channels, ASICs)。酸敏感离子通道是一类可以被胞外H+激活的阳离子通道,目前为止共发现了6种ASICs蛋白亚型,分别分别由4种基因编码。组织酸化诱发ASICs开放,乳酸堆积以及炎症因子的释放导致ASICs电流增大,大量Na+内流,导致细胞水肿。已有文献报道,同聚体酸敏感离子通道1a亚型(ASICla)通道对Ca2+有较大的通透性,加重胞内Ca2+超载,引起神经元死亡,缺血坏死区增大。尽管已知ASICs,尤其ASICla是脑缺血中非谷氨酸依赖性Ca2+毒性和脑损伤的主要参与者,目前对于ASICs在脑缺血损伤作用机制并不明确,寻找可用于临床的抑制ASICs的有效药物也是难点之一。
本论文建立了大鼠海马神经细胞酸中毒模型,在该模型上引入缺氧缺糖(oxygen-glucose deprivation, OGD)和再灌注(reperfusion)的方法,综合应用膜片钳技术、激光共聚焦显微成像技术结合凋亡/坏死特异性检测手段,研究ASICs以及ASICla在酸中毒引起细胞损伤中的作用机制,酸中毒在OGD及再灌注过程中的损伤作用及ASICs在其中的调控机制,为进一步研究酸中毒在脑缺血性中风中的作用奠定基础。同时以常用的中风治疗药物葛根素为对象,研究中药在酸中毒损伤中的保护作用及对ASICs的调控机制。为开发新型的中风治疗药物提供新的思路和靶点。
本论文的主要研究结果有：
1.建立稳定的酸中毒损伤模型,并判断酸敏感离子通道(ASICs)是否参与酸中毒引起的神经元损伤。实验发现以pH6.0的胞外液造模4小时后,ASICs的阻断剂amiloride以及ASICla的特异性阻断剂PcTxl均能抑制酸中毒引起的神经元损伤,改善神经元活性。
2.建立稳定简易的快速给药、灌流系统,结合膜片钳离子通道电流检测技术,检测胞外pH下降对大鼠海马神经元电活动的影响。实验发现胞外pH下降能引起一个幅值较大的慢激活、慢失活的内向电流。ASICs抑制剂amiloride能浓度依赖性地抑制该电流,其最大半数激活电流浓度分别为13.8μM,因此判断胞外pH快速下降激活的通道是ASICs.
3.实验发现胞外酸环境能抑制培养了12天以后的神经元产生的自发电流,而这种自发电流是非ASICs依赖性的。
4.葛根素对酸中毒损伤中的海马神经元具有保护作用。葛根素与PcTxl联用并不能进一步改善神经元的活性,降低神经元的死亡率。而电生理实验也证明葛根素对ASICs以及ASICla均具有浓度依赖性的抑制作用,由此推测葛根素通过抑制ASICs尤其是ASICla通道的开放保护酸中毒损伤中的神经元。
5.实验发现,OGD和再灌注过程中,酸中毒均引起了神经元的损伤,然而与OGD相比,再灌注过程中酸中毒损伤显著加剧。在OGD过程中使用amiloride和PcTxl均没有保护作用,但在再灌注过程中,amiloride和PcTxl均能改善酸中毒引起的细胞损伤,由此推测脑缺血/再灌注中,ASICs,尤其是ASICla的开放对神经元的损伤作用主要发生在再灌注时期,而非缺血时期。此外,电生理实验发现,OGD时,胞外pH快速下降并不改变海马神经元上ASICs通道的幅值、失活时间常数,但是ASICs从脱敏状态恢复至关闭状态的时间大大延长,其恢复时间常数从16.12±2.18s延长至69.54±21.10s,由此引起ASICs开放频率的大大下降,这可能是ASICs在OGD时并不起主要作用的原因。
综上所述,本研究的发现是：1)ASICs参与了酸中毒引起的神经元损伤,但是ASICs没有参与酸中毒引起的神经元自发电流的降低；2)葛根素对酸中毒引起的神经元损伤具有保护作用,其作用机制是浓度依赖性的抑制ASICs,尤其是ASICla通道电流；3)缺血再灌注过程中,酸中毒在缺血过程中引起神经元的损伤,再灌注显著加剧了神经元损伤；4)ASICs主要在再灌注时期参与了神经元损伤,导致这一现象的原因是OGD非常显著地延长了ASICs从脱敏状态恢复的时间,由此导致ASICs开放频率的下降。这些结果提示ASICs在脑缺血/再灌注过程中可能起了重要作用,以及葛根素在这一过程中保护神经元的可能机制,具有创新性。
Ischemic stroke is one of the major causes of human death and disabilities with main parthological mechanism of neuronal injury by ischemia. Acidosis is a common feature of ischemic brain. Accumulation of lactic acid as a byproduct of glycolysis and protons produced by ATP hydrolysis cause extracellular pH reduction during brain ischemia. Acidosis lasts for more than 4 hours with a pH below 6.0 under hyperglycemic conditions, which is expected to activate acid-sensing ion channels (ASICs). ASICs, which are activated by extracellular acidosis and mainly permeate Na+ currents, are members of Deg/ENaC super family. Up to now, six different ASIC isoforms, derived from four genes, have been identified. It has been reported that the wide spread expression of ASIC1a, which is the only acid sensing ion channel that conducts Ca2+, gives us a new clue to glutamate-independent intracellular Ca2+ accumulation and neuronal injury during ischemia. Although ASICs, especially ASIC1a, are considered to be new targets for brain ischemia, few drugs have been shown to effectively inhibit ASIC currents. The injury mechanisms of ASICs during ischemia and reperfusion also remain illuminated.
In this study, we developed an in vitro acidotic model in rat hippocampal neurons. We investigated the effect of ASICs and ASIC1a during acidosis using techniques of patch clamp and laser scanning microscopy of confocal (LSMC).We also applied oxygen-glucose deprivation (OGD) and reperfusion during acidosis to simulate in vivo ischemia/reperfusion. The modulatory effect of ASICs on cell viability during OGD or reperfusion-companied acidosis was determined. The mechanism of ASICs modulated by OGD was also investigated. In the meantime, the modulatory effect of puerarin on ASICs and ASIC1a was also delineated, providing a mechanical insight into neuroprotective effect of puerarin during brain ischemia.
The main results of this study are:
1. Both amiloride, inbitor of ASICs and PcTxl,specific blocker of ASIC1a were able to protect hippocampal neurons from acidotic injuries.
2. A home-made'Y'-tube perfusion system was employed to achieve a rapid extracellular solution change. The fast reduction extracellular pH induced a large inward current that was slow activated and slow inactivated, which could be dose-dependently inhibited by amiloride with IC50 of 13.8μM. This confirmed that the inwared current was ASICs.
3. Extracellular acidosis was able to inhibit spontaneous current in 12-day cultured neurons. This inhibition was ASICs-independent.
4. Puerarin could protect hippocampal neurons from acidotic injuries. Electrophysiological experiments showed that puerarin inhibit ASICs and ASIC1a current in a dose-dependent way with IC50 of 38.4μM and 9.31μM, indicating that puerarin prtected neurons by a mechanism of inhibing ASICs, especially ASIC1a.
5. Acidosis induced neuronal damage during both OGD and reperfusion. However, it caused more detrimental injury during reperfusion. Application of neither amiloride nor PcTxl could protect neurons during OGD, while application of either amiloride or PcTxl improve neuronal viability during reperfusion. This result showed that the opening of ASICs, especially ASIC1a, induced cell injury during reperfusion other than ischemia. On the other hand, neither the amplitude nor desensitization of ASICs changed during OGD.
Nevertheless, the recovery of ASICs from desensitization slowed down from 16.12±2.18s during normoxia to 69.54±21.10s during OGD, resulting to a reduced opening frequency of ASICs. This may be the protective mechanism of OGD from the acidotic injuries.
In conclution, our results suggested that ASICs took part in the neuronal injuries during acidosis, but did not take part in the the acidosis-induced reduce of spontaneous currents. Futhermore, we also showed that OGD slowed down recovery of ASICs from desensitization, which may result the more detrimental effect of reperfusion during acidosis. On the other hand, puerarin protected neurons from acidotic injuries probably by inhibiting ASICs and ASIC1a. These results indicated that ASICs play an important role during ischemia/reperfusion, which gave us a new clue to drug development for stroke.
本论文建立了大鼠海马神经细胞酸中毒模型,在该模型上引入缺氧缺糖(oxygen-glucose deprivation, OGD)和再灌注(reperfusion)的方法,综合应用膜片钳技术、激光共聚焦显微成像技术结合凋亡/坏死特异性检测手段,研究ASICs以及ASICla在酸中毒引起细胞损伤中的作用机制,酸中毒在OGD及再灌注过程中的损伤作用及ASICs在其中的调控机制,为进一步研究酸中毒在脑缺血性中风中的作用奠定基础。同时以常用的中风治疗药物葛根素为对象,研究中药在酸中毒损伤中的保护作用及对ASICs的调控机制。为开发新型的中风治疗药物提供新的思路和靶点。
本论文的主要研究结果有：
1.建立稳定的酸中毒损伤模型,并判断酸敏感离子通道(ASICs)是否参与酸中毒引起的神经元损伤。实验发现以pH6.0的胞外液造模4小时后,ASICs的阻断剂amiloride以及ASICla的特异性阻断剂PcTxl均能抑制酸中毒引起的神经元损伤,改善神经元活性。
2.建立稳定简易的快速给药、灌流系统,结合膜片钳离子通道电流检测技术,检测胞外pH下降对大鼠海马神经元电活动的影响。实验发现胞外pH下降能引起一个幅值较大的慢激活、慢失活的内向电流。ASICs抑制剂amiloride能浓度依赖性地抑制该电流,其最大半数激活电流浓度分别为13.8μM,因此判断胞外pH快速下降激活的通道是ASICs.
3.实验发现胞外酸环境能抑制培养了12天以后的神经元产生的自发电流,而这种自发电流是非ASICs依赖性的。
4.葛根素对酸中毒损伤中的海马神经元具有保护作用。葛根素与PcTxl联用并不能进一步改善神经元的活性,降低神经元的死亡率。而电生理实验也证明葛根素对ASICs以及ASICla均具有浓度依赖性的抑制作用,由此推测葛根素通过抑制ASICs尤其是ASICla通道的开放保护酸中毒损伤中的神经元。
5.实验发现,OGD和再灌注过程中,酸中毒均引起了神经元的损伤,然而与OGD相比,再灌注过程中酸中毒损伤显著加剧。在OGD过程中使用amiloride和PcTxl均没有保护作用,但在再灌注过程中,amiloride和PcTxl均能改善酸中毒引起的细胞损伤,由此推测脑缺血/再灌注中,ASICs,尤其是ASICla的开放对神经元的损伤作用主要发生在再灌注时期,而非缺血时期。此外,电生理实验发现,OGD时,胞外pH快速下降并不改变海马神经元上ASICs通道的幅值、失活时间常数,但是ASICs从脱敏状态恢复至关闭状态的时间大大延长,其恢复时间常数从16.12±2.18s延长至69.54±21.10s,由此引起ASICs开放频率的大大下降,这可能是ASICs在OGD时并不起主要作用的原因。
综上所述,本研究的发现是：1)ASICs参与了酸中毒引起的神经元损伤,但是ASICs没有参与酸中毒引起的神经元自发电流的降低；2)葛根素对酸中毒引起的神经元损伤具有保护作用,其作用机制是浓度依赖性的抑制ASICs,尤其是ASICla通道电流；3)缺血再灌注过程中,酸中毒在缺血过程中引起神经元的损伤,再灌注显著加剧了神经元损伤；4)ASICs主要在再灌注时期参与了神经元损伤,导致这一现象的原因是OGD非常显著地延长了ASICs从脱敏状态恢复的时间,由此导致ASICs开放频率的下降。这些结果提示ASICs在脑缺血/再灌注过程中可能起了重要作用,以及葛根素在这一过程中保护神经元的可能机制,具有创新性。
Ischemic stroke is one of the major causes of human death and disabilities with main parthological mechanism of neuronal injury by ischemia. Acidosis is a common feature of ischemic brain. Accumulation of lactic acid as a byproduct of glycolysis and protons produced by ATP hydrolysis cause extracellular pH reduction during brain ischemia. Acidosis lasts for more than 4 hours with a pH below 6.0 under hyperglycemic conditions, which is expected to activate acid-sensing ion channels (ASICs). ASICs, which are activated by extracellular acidosis and mainly permeate Na+ currents, are members of Deg/ENaC super family. Up to now, six different ASIC isoforms, derived from four genes, have been identified. It has been reported that the wide spread expression of ASIC1a, which is the only acid sensing ion channel that conducts Ca2+, gives us a new clue to glutamate-independent intracellular Ca2+ accumulation and neuronal injury during ischemia. Although ASICs, especially ASIC1a, are considered to be new targets for brain ischemia, few drugs have been shown to effectively inhibit ASIC currents. The injury mechanisms of ASICs during ischemia and reperfusion also remain illuminated.
In this study, we developed an in vitro acidotic model in rat hippocampal neurons. We investigated the effect of ASICs and ASIC1a during acidosis using techniques of patch clamp and laser scanning microscopy of confocal (LSMC).We also applied oxygen-glucose deprivation (OGD) and reperfusion during acidosis to simulate in vivo ischemia/reperfusion. The modulatory effect of ASICs on cell viability during OGD or reperfusion-companied acidosis was determined. The mechanism of ASICs modulated by OGD was also investigated. In the meantime, the modulatory effect of puerarin on ASICs and ASIC1a was also delineated, providing a mechanical insight into neuroprotective effect of puerarin during brain ischemia.
The main results of this study are:
1. Both amiloride, inbitor of ASICs and PcTxl,specific blocker of ASIC1a were able to protect hippocampal neurons from acidotic injuries.
2. A home-made'Y'-tube perfusion system was employed to achieve a rapid extracellular solution change. The fast reduction extracellular pH induced a large inward current that was slow activated and slow inactivated, which could be dose-dependently inhibited by amiloride with IC50 of 13.8μM. This confirmed that the inwared current was ASICs.
3. Extracellular acidosis was able to inhibit spontaneous current in 12-day cultured neurons. This inhibition was ASICs-independent.
4. Puerarin could protect hippocampal neurons from acidotic injuries. Electrophysiological experiments showed that puerarin inhibit ASICs and ASIC1a current in a dose-dependent way with IC50 of 38.4μM and 9.31μM, indicating that puerarin prtected neurons by a mechanism of inhibing ASICs, especially ASIC1a.
5. Acidosis induced neuronal damage during both OGD and reperfusion. However, it caused more detrimental injury during reperfusion. Application of neither amiloride nor PcTxl could protect neurons during OGD, while application of either amiloride or PcTxl improve neuronal viability during reperfusion. This result showed that the opening of ASICs, especially ASIC1a, induced cell injury during reperfusion other than ischemia. On the other hand, neither the amplitude nor desensitization of ASICs changed during OGD.
Nevertheless, the recovery of ASICs from desensitization slowed down from 16.12±2.18s during normoxia to 69.54±21.10s during OGD, resulting to a reduced opening frequency of ASICs. This may be the protective mechanism of OGD from the acidotic injuries.
In conclution, our results suggested that ASICs took part in the neuronal injuries during acidosis, but did not take part in the the acidosis-induced reduce of spontaneous currents. Futhermore, we also showed that OGD slowed down recovery of ASICs from desensitization, which may result the more detrimental effect of reperfusion during acidosis. On the other hand, puerarin protected neurons from acidotic injuries probably by inhibiting ASICs and ASIC1a. These results indicated that ASICs play an important role during ischemia/reperfusion, which gave us a new clue to drug development for stroke.
引文
[1]张均田,神经药理学研究进展,北京：人民卫生出版社,2002.
[2]王维治,神经病学,人民卫生出版社,2006.
[3]B.K. Siesjo, K. Katsura, and T. Kristian, Acidosis-related damage. Adv Neurol 71(1996) 209-33; discussion 234-6.
[4]B. Siesjo, Acidosis and ischemic brain damage. Neurochem Pathol 9 (1998) 31-88.
[5]Z.G. Xiong, X.M. Zhu, X.P. Chu, M. Minami, J. Hey, W.L. Wei, J.F. MacDonald, J.A. Wemmie, M.P. Price, M.J. Welsh, and R.P. Simon, Neuroprotection in ischemia:blocking calcium-permeable acid-sensing ion channels. Cell 118 (2004) 687-698.
[6]O. Yermolaieva, A.S. Leonard, M.K. Schnizler, F.M. Abboud, and M.J. Welsh, Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel la. Proc Natl Acad Sci U S A 101 (2004) 6752-7.
[7]贾建平,神经病学,北京大学医学出版社,2004.
[8]杨渊,and张苏明,脑缺血的病理生理研究进展：半暗带、基因表达与神经元保护.国外医学(物理医学与康复学分册)23(2003).
[9]U. Dirnagl, C. Iadecola, and M.A. Moskowitz, Pathobiology of ischaemic stroke:an integrated view. Trends Neurosci 22 (1999) 391-7.
[10]B. Siesjo, Pachophysiology and treatment forcal cerebral ischemia. Part Ⅱ: Mechanisms of damage and treatment.. J Neurosurg 77 (1992) 337-54.
[11]L. Hertz, Bioenergetics of cerebral ischemia:A cellular perspective. Neuropharmacology 55 (2008) 289-309.
[12]J.M. Pocock, and D.G. Nicholls, Exocytotic and nonexocytotic modes of glutamate release from cultured cerebellar granule cells during chemical ischaemia. J Neurochem 70 (1998) 806-13.
[13]D.J. Rossi, T. Oshima, and D. Attwell, Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 403 (2000) 316-21.
[14]R.L. Macdonald, and M. Stoodley, Pathophysiology of cerebral ischemia. Neurol Med Chir (Tokyo) 38 (1998) 1-11.
[15]P. Lipton, Ischemic Cell Death in Brain Neurons. Physiol Rev 79 (1999) 1431-568.
[16]A. Mitani, S. Takeyasu, H. Yanase, Y. Nakamura, and K. Kataoka, Changes in intracellular Ca2+ and energy levels during in vitro ischemia in the gerbil hippocampal slice. J Neurochem 62 (1994) 626-34.
[17]D.J. McConkey, and S. Orrenius, The role of calcium in the regulation of apoptosis. Biochem Biophys Res Commun 239 (1997) 357-66.
[18]A. Diarra, C. Sheldon, C.L. Brett, K.G. Baimbridge, and J. Church, Anoxia-evoked intracellular pH and Ca2+ concentration changes in cultured postnatal rat hippocampal neurons. Neuroscience 93 (1999) 1003-16.
[19]H.A. Kontos, Oxygen radicals in cerebral ischemia:the 2001 Willis lecture. Stroke 32 (2001) 2712-6.
[20]G.H. Danton, and W.D. Dietrich, Inflammatory mechanisms after ischemia and stroke. J Neuropathol Exp Neurol 62 (2003) 127-36.
[21]G.Y. Yang, G.P. Schielke, C. Gong, Y. Mao, H.L. Ge, X.H. Liu, and A.L. Betz, Expression of tumor necrosis factor-alpha and intercellular adhesion molecule-1 after focal cerebral ischemia in interleukin-lbeta converting enzyme deficient mice. J Cereb Blood Flow Metab 19 (1999) 1109-17.
[22]G. Cao, M. Minami, W. Pei, C. Yan, D. Chen, C. O'Horo, S.H. Graham, and J. Chen, Intracellular Bax translocation after transient cerebral ischemia: implications for a role of the mitochondrial apoptotic signaling pathway in ischemic neuronal death. J Cereb Blood Flow Metab 21 (2001) 321-33.
[23]L.L. Dugan, S.L. Sensi, L.M. Canzoniero, S.D. Handran, S.M. Rothman, T.S. Lin, M.P. Goldberg, and D.W. Choi, Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-D-aspartate. J Neurosci 15 (1995) 6377-88.
[24]N. Vila, J. Castillo, A. Davalos, and A. Chamorro, Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke 31 (2000) 2325-9.
[25]王军,大鼠脑缺血模型研究进展.中医研究 15(2002)60-62.
[26]O.A. Kryshtal, and V.I. Pidoplichko, Proton receptor in a nerve cell membrane. Dokl Akad Nauk SSSR 255 (1980) 1494-6.
[27]E.Z. Longa, P.R. Weinstein, S. Carlson, and R. Cummins, Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20 (1989) 84-91.
[28]M.P. Goldberg, H. Monyer, J.H. Weiss, and D.W. Choi, Adenosine reduces cortical neuronal injury induced by oxygen or glucose deprivation in vitro. Neurosci Lett 89 (1988) 323-7.
[29]翁骏,and吕秋军,药物代谢稳定性筛选的研究进展.国外医学(药学分册)33(2006)211-214.
[30]杜冠华,高通量药物筛选技术进展与新药开发策略 中国新药杂志 11(2002)31-36.
[31]M. Chesler, The regulation and modulation of pH in the nervous system. Prog Neurobiol 34 (1990) 401-27.
[32]S. Rehncrona, Brain acidosis. Ann Emerg Med 14 (1985) 770-6.
[33]R. Waldmann, G. Champigny, F. Bassilana, C. Heurteaux, and M. Lazdunski, A proton-gated cation channel involved in acid-sensing. Nature 386 (1997) 173-177.
[34]C.C. Chen, S. England, A.N. Akopian, and J.N. Wood, A sensory neuron-specific, proton-gated ion channel. Proc Natl Acad Sci U S A 95 (1998) 10240-10245.
[35]J.A. Saugstad, J.A. Roberts, J. Dong, S. Zeitouni, and R.J. Evans, Analysis of the Membrane Topology of the Acid-sensing Ion Channel 2a. J Biol Chem 279(2004)55514-55519.
[36]R. Waldmann, and M. Lazdunski, H(+)-gated cation channels:neuronal acid sensors in the NaC/DEG family of ion channels. Curr. Opin. Neurobiol.8 (1998)418-24.
[37]D.A. de la Rosa, C.M. Canessa, G.K. Fyfe, and P. Zhang, Structure and Regulation of Amiloride-Sensitive Sodium Channels. Annu Rev Physiol 62 (2000) 573-594.
[38]B.K. Berdiev, T.B. Mapstone, J.M. Markert, Y. Gillespie, J. Lockhart, C.M. Fuller, and D.J. Benos, pH Alterations "Reset" Ca2+ Sensitivity of Brain Na+ Channel 2, a Degenerin/Epithelial Na+ Ion Channel, in Planar Lipid Bilayers. Journal of Biological Chemistry 276 (2001) 38755-38761.
[39]E. Babini, M. Paukert, H.-S. Geisler, and S. Grunder, Alternative splicing and interaction with di-and polyvalent cations control the dynamic range of acid-sensing ion channel (ASIC) 1 J. Biol. Chem (2002).
[40]D. Immke, and E. McCleskey, Protons open acid-sensing ion channels by catalyzing relief of Ca2+ blockade. Neuron 37 (2003) 75-84.
[41]J.d. Weille, and F. Bassilana, Dependence of the acid-sensitive ion channel, ASICla, on extracellular Ca2+ ions Brain Research 900 (2001) 277-281
[42]H. Cadiou, M. Studer, N.G. Jones, E.S.J. Smith, A. Ballard, S.B. McMahon, and P.A. McNaughtop, Modulation of Acid-Sensing Ion Channel Activity by Nitric Oxide. J Neurosci 27 (2007) 13251-13260.
[43]J. Gao, B. Duan, D.G. Wang, X.H. Deng, G.Y. Zhang, L. Xu, and T.L. Xu, Coupling between NMDA Receptor and Acid-Sensing Ion Channel Contributes to Ischemic Neuronal Death. Neuron 48 (2005) 635-646.
[44]O. Krishtal, The ASICs:Signaling molecules? Modulators?. Trends in Neurosciences 26 (2003) 477-483
[45]J. Jasti, H. Furukawa, E.B. Gonzales, and E. Gouaux, Structure of acid-sensing ion channel 1 at 1.9A resolution and low pH. Nature 449 (2007)316-323.
[46]Yang H, Yu Y, Li W, Xu T, and J. H, Inherent dynamics of the acid-sensing ion channel 1 correlates with the gating mechanism. PLoS Biol 7 (2009) e1000151.
[47]E. Lingueglia, J.R. de Weille, F. Bassilana, C. Heurteaux, H. Sakai, R. Waldmann,and M. Lazdunski, A Modulatory Subunit of Acid Sensing Ion Channels in Brain and Dorsal Root Ganglion Cells. J. Biol. Chem.272 (1997) 29778-29783.
[48]M. Ettaiche, N. Guy, P. Hofman, M. Lazdunski, and R. Waldmann, Acid-Sensing Ion Channel 2 Is Important for Retinal Function and Protects against Light-Induced Retinal Degeneration. J Neurosci 24 (2004) 1005-1012.
[49]D.A. de la Rosa, S.R. Krueger, A. Kolar, D. Shao, R.M. Fitzsimonds, and C.M. Canessa, Distribution, subcellular localization and ontogeny of ASIC1 in the mammalian central nervous system. J Physiol 546 (2003) 77-87.
[50]J.A. Wemmie, J. Chen, C.C. Askwith, A.M. Hruska-Hageman, M.P. Price, B.C. Nolan, P.G. Yoder, E. Lamani, T. Hoshi, J.H. Freeman, and M.J. Welsh, The Acid-Activated Ion Channel ASIC Contributes to Synaptic Plasticity, Learning, and Memory. Neuron 34 (2002) 463-77.
[51]C. Roza, J.-L. Puel, M. Kress, A. Baron, S. Diochot, M. Lazdunski, and R. Waldmann, Knockout of the ASIC2 channel in mice does not impair cutaneous mechanosensation, visceral mechanonociception and hearing. J Physiol 558 (2004) 659-669
[52]S. Ugawa, Y. Minami, W. Guo, Y. Saishin, K. Takatsuji, T. Yamamoto, M. Tqhyama, and S. Shimada, Receptor that leaves a sour taste in the mouth. Nature 395 (1998) 555-6.
[53]R. Waldmann, F. Bassilana, J. de Weille, G. Champigny, C. Heurteaux, and M. Lazdunski, Molecular Cloning of a Non-inactivating Proton-gated Na+ Channel Specific for Sensory Neurons. J Biol Chem 272 (1997) 20975-20978.
[54]Q.Y. Meng, W. Wang, X.N. Chen, T.L. Xu, and J.N. Zhou, Distribution of acid-sensing ion channel 3 in the rat hypothalamus. Neurosci 159 (2009) 1126-1134.
[55]S.P. Sutherland, C.J. Benson, J.P. Adelman, and E.W. McCleskey, Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons,2001, pp.711-716.
[56]A.N. Akopian, C.-C. Chen, Y. Ding, P. Cesare, and J.N. Wood, A new member of the acid-sensing ion channel family. Neuroreport 11 (2000) 2217-22.
[57]S. Grander, H.-S. Geissler, E.-L. Bessler, and J.P. Ruppersberg, A new member of acid-sensing ion channels from pituitary gland. NeuroReport 11(2000)1607-1611.
[58]伍龙军,and徐天乐,酸敏感离子通道研究进展.生物化学与生物物理进展29(2002)197-203.
[59]C. Askwith, J. Wemmie, M. Price, T. Rokhlina, and M. Welsh, Acid-sensing ion channel 2 (ASIC2) modulates ASIC1 H+-activated currents in hippocampal neurons. J Biol Chem 279 (2004) 18296-305.
[60]A. Baron, R. Waldmann, and M. Lazdunski, ASIC-like, proton-activated currents in rat hippocampal neurons. J Physiol 539 (2002) 485-494.
[61]B.K. Berdiev, J. Xia, L.A. McLean, J.M. Markert, G.Y. Gillespie, T.B. Mapstone, A.P. Naren, B. Jovov, J.K. Bubien, H.-L. Ji, C.M. Fuller, K.L Kirk, and D.J. Benos, Acid-sensing Ion Channels in Malignant Gliomas J. Biol. Chem.278 (2003) 15023-15034.
[62]J.-H. Yea, J. Gaoc, Y.-N. Wub, Y.-J. Hua, C.-P. Zhanga, and T.-L. Xu, Identification of acid-sensing ion channels in adenoid cystic carcinomas. Biochem Biophys Res Commun 355 (2007 April 20) 986-992
[63]X. Su, Q. Li, K. Shrestha, E. Cormet-Boyaka, L. Chen, P.R. Smith, E.J. Sorscher, D.J. Benos, S. Matalon, and H.-L. Ji, Interregulation of Proton-gated Na+ Channel 3 and Cystic Fibrosis Transmembrane Conductance Regulator. J Biol Chem 281 (2006) 36960-36968.
[64]袁凤来,陈飞虎,李霞,黄学应,吴繁荣,张腾跃,吕元庆,and李俊,重组人内抑素对佐剂性关节炎大鼠关节软骨酸敏感离子通道的影响及其保护作用 中国药理学通报 24(2008)893-897.
[65]袁凤来,陈飞虎,黄学应,李霞,吴繁荣,阮晶晶,and李俊,酸敏感离子通道在大鼠佐剂性关节炎关节软骨中的表达 中华风湿病学杂志12(2008)321-325.
[66]P.W. Reeh, and M. Kress, Molecular physiology of proton transduction in nociceptors. Curr Opin Pharmacol 1 (2001)45-51.
[67]M. Ettaiche, E. Deval, M. Cougnon, M. Lazdunski, and N. Voilley, Silencing Acid-Sensing Ion Channel 1a Alters Cone-Mediated Retinal Function. J Neurosci 26 (2006) 5800-5809.
[68]M. Driscoll, and M. Chalfie, The mec-4 gene is a member of a family of Caenorhabditis elegans genes that can mutate to induce neuronal degeneration. Nature 349 (1991) 588-93.
[69]M.P. Price, GR. Lewin, S.L. Mcllwrath, C. Cheng, J. Xie, P.A. Heppenstall, C.L. Stucky, A.G. Mannsfeldt, T.J. Brennan, H.A. Drummond, J. Qiao, C.J. Benson, D.E. Tarr, R.F. Hrstka, B. Yang, R.A. Williamson, and M.J. Welsh, The mammalian sodium channel BNC1 is required for normal touch sensation. Nature 407 (2000) 1007-11.
[70]L. Liu, and S.A. Simon, Acidic stimuli activates two distinct pathways in taste receptor cells from rat fungiform papillae. Brain Res 923 (2001) 58-70.
[71]J.G. Brand, Cloning and expression of an ASIC1 from human taste tissue. in: K. Persaud, and S. Van Toller, (Eds.), International Symposium on Olfaction and Taste, European Chemoreception Research Organisation, Brighton, UK,2000, pp.80.
[72]W. Lennox, The effect on epileptic seizures of varying the composition of the respired air. J Clin Invest 4 (1929) 23-24.
[73]L. Velisek, J. Dreier, P. Stanton, U. Heinemann, and S. Moshe, Lowering of extracellular pH suppresses low-Mg2+-induced seizures in combined entorhinal cortex-hiipocampal slices. Exp. Brain Res 101 (1994) 44-52.
[74]A.E. Ziemann, M.K. Schnizler, G.W. Albert, M.A. Severson, M.A. Howard Iii, M.J. Welsh, and J.A. Wemmie, Seizure termination by acidosis depends on ASIC1a. Nat Neurosci 11 (2008) 816-822.
[75]Z.Q. Xiong, and J.L. Stringer, Extracellular pH responses in CA1 and the dentate gyrus during electrical stimulation, seizure discharges, and spreading depression. J Neurophysiol 83 (2000) 3519-24.
[76]G. Biaginib, K. Babinskid, M. Avoli, M. Marcinkiewicz, and P. Seguela, Regional and Subunit-Specific Downregulation of Acid-Sensing Ion Channels in the Pilocarpine Model of Epilepsy Neurobiology of Disease 8 (2001) 45-48.
[77]N.G. Prosper, Amiloride delays the onset of pilocarpine-induced seizures in rats. Brain Research 1222 (2008) 230-232.
[78]M.B. Graebera, and U. Miillerb, Recent developments in the molecular genetics of mitochondrial disorders J Neurol Sci 153 (1998)251-63.
[79]A. Bender, K. Krishnan, C. Morris, G. Taylor, A. Reeve, R. Perry, E. Jaros, J. Hersheson, J. Betts, T. Klopstock, R. Taylor, and D. Turnbull, High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson's disease. Nat. Genet 38 (2006) 515-517.
[80]S.E. Browne, and M.F. Beal, The energetics of Huntington's disease. Neurochem Res 29 (2004) 531-546.
[81]M.A. Friese, M.J. Crane, R. Etzensperger, S. Vergo, J.A. Wemmie, M.J. Welsh, A. Vincent, and L. Fugge, Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nature Medicine 13 (2007) 1483-1489
[82]R.L. Arias, M.L. Sung, D. Vasylyev, M.Y. Zhang, K. Albinson, K. Kubek, N. Kagan, C. Beyer, Q. Lin, J.M. Dwyer, M.M. Zaleska, M.R. Bowlby, J. Dunlop, and M. Monaghan, Amiloride is neuroprotective in an MPTP model of Parkinson's disease. Neurobiol Dis 31 (2008) 334-41.
[83]H. Wong, P. Bauer, M. Kurosawa, A. Goswami, C. Washizu, Y. Machida, A. Tosaki, M. Yamada, T. Knopfel, T. Nakamura, and N. Nukina, Blocking acid-sensing ion channel 1 alleviates Huntington's disease pathology via an ubiquitin-proteasome system-dependent mechanism. Hum Mol Genet 17(2008)3223-35.
[84]D.C. Immke, and E.W. McCleskey, Lactate enhances the acid-sensing Na+ channel on ischemia-sensing neurons. Nat Neurosci 4 (2001) 869-870.
[85]N. Voilley, J. de Weille, J. Mamet, and M. Lazdunski, Nonsteroid Anti-Inflammatory Drugs Inhibit Both the Activity and the Inflammation-Induced Expression of Acid-Sensing Ion Channels in Nociceptors. J Neurosci 21 (2001) 8026-8033.
[86]J. Mamet, A. Baron, M. Lazdunski, and N. Voilley, ProInflammatory Mediators, Stimulators of Sensory Neuron Excitability via the Expression of Acid-Sensing Ion Channels. J Neurosci 22 (2002) 10662-10670.
[87]G. Pignataro, R.P. Simon, and Z.G. Xiong, Prolonged activation of ASIC1a and the time window for neuroprotection in cerebral ischemia. Brain 130 (2007) 151-158.
[88]Z.G. Xiong, G. Pignataro, M. Li, S. Chang, and R.P. Simon, Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases Curr Opin Pharmacol 8 (2008)25-32.
[89]J.S. Mogil, N.M. Breese, M.-F. Witty, J. Ritchie, M.-L. Rainville, A. Ase, N. Abbadi, C.L. Stucky, and P. Seguela, Transgenic Expression of a Dominant-Negative ASIC3 Subunit Leads to Increased Sensitivity to Mechanical and Inflammatory Stimuli. J Neurosci 25 (2005) 9893-9901.
[90]E. Deval, J. Noel, N. Lay, A. Alloui, S. Diochot, V. Friend, M. Jodar, M. Lazdunski, and E. Lingueglia, ASIC3, a sensor of acidic and primary inflammatory pain. EMBO J 27 (2008) 3047-55.
[91]M. Mazzuca, C. Heurteaux, A. Alloui, S. Diochot, A. Baron, N. Voilley, N. Blondeau, P. Escoubas, A. Gelot, A. Cupo, A. Zimmer, A.M. Zimmer, A. Eschalier, and M. Lazdunski, A tarantula peptide against pain via ASIC1a channels and opioid mechanisms. Nat Neurosci 10 (2007) 943-945.
[92]B. Duan, L.-J. Wu, Y.-Q. Yu, Y. Ding, L. Jing, L. Xu, J. Chen, and T.-L. Xu, Upregulation of Acid-Sensing Ion Channel ASIC1a in Spinal Dorsal Horn Neurons Contributes to Inflammatory Pain Hypersensitivity. J Neurosci 27 (2007)11139-11148.
[93]A.A. Staniland, and S.B. McMahon, Mice lacking acid-sensing ion channels (ASIC) 1 or 2, but not ASIC3, show increased pain behaviour in the formalin test. EurJ Pain 13 (2009) 554-563
[94]S. Gregoire, and J. Matricon, Differential Involvement of ASIC1a in the Basolateral Amygdala in Fear Memory and Unconditioned Fear Responses. J. Neurosci 29 (2009) 6053-6054.
[95]M.W. Coryell, A.M. Wunsch, J.M. Haenfler, J.E. Allen, J.L. McBride, B.L. Davidson, and J.A. Wemmie, Restoring Acid-Sensing Ion Channel-la in the Amygdala of Knock-Out Mice Rescues Fear Memory But Not Unconditioned Fear Responses. J Neurosci 28 (2008) 13738-13741.
[96]M.W. Coryell, A.E. Ziemann, P.J. Westmoreland, J.M. Haenfler, Z. Kurjakovic, X.M. Zha, M. Price, M.K. Schnizler, and J.A. Wemmie, Targeting ASIC1a Reduces Innate Fear and Alters Neuronal Activity in the Fear Circuit. Biol Psychiatry 62 (2007) 1140-1148.
[97]J.A. Wemmie, M.W. Coryell, C.C. Askwith, E. Lamani, A.S. Leonard, C.D. Sigmund, and M.J. Welsh, Overexpression of acid-sensing ion channel la in transgenic mice increases acquired fear-related behavior.101 (2004) 3621-3626.
[98]M.W. Coryell, A.M.Wunsch,J.M. Haenfler, J.E. Allen, M. Schnizler, A.E. Ziemann, M.N. Cook, J.P. Dunning, M.P. Price, J.D. Rainier, Z. Liu, A.R. Light, D.R. Langbehn, and J.A. Wemmie, Acid-Sensing Ion Channel-1a in the Amygdala, a Novel Therapeutic Target in Depression-Related Behavior. J. Neurosci 29 (2009) 5381-5388.
[99]T.R. Kleyman, and E.J. Cragoe, Jr., Amiloride and its analogs as tools in the study of ion transport. J Membr Biol 105 (1988) 1-21.
[100]S. Attaphitaya, K. Park, and J.E. Melvin, Molecular Cloning and Functional Expression of a Rat Na+/H+ Exchanger (NHE5) Highly Expressed in Brain. J Biol Chem 274 (1999) 4383-4388.
[101]R. Waldmann, G. Champigny, N. Voilley, I. Lauritzen, and M. Lazdunski, The Mammalian Degenerin MDEG, an Amiloride-sensitive Cation Channel Activated by Mutations Causing Neurodegeneration in Caenorhabditis elegans. J Biol Chem 271 (1996) 10433-10436.
[102]M. Vukicevic, and S. Kellenberger, Modulatory effects of acid-sensing ion channels on action potential generation in hippocampal neurons. AM J Physiol-CELL PH 287 (2004) 682-690.
[103]Wu LJ, Duan B, Mei YD, Gao J, Chen JQ Zhuo M, Xu L, Wu M, and X. TL, Characterization of acid-sensing ion channels in dorsal horn neurons of rat spinal cord. J Biol Chem 279 (2004) 43716-43724.
[104]L. Schild, E. Schneeberger, I. Gautschi, and D. Firsov, Identification of amino acid residues in the alpha, beta, and gamma subunits of the epithelial sodium channel (ENaC) involved in amiloride block and ion permeation. J Gen Physiol 109 (1997) 15-26.
[105]G. Champigny, N. Voilley, R. Waldmann, and M. Lazdunski, Mutations causing neurodegeneration in Caenorhabditis elegans drastically alter the pH sensitivity and inactivation of the mammalian H+-gated Na+ channel MDEG1.J Biol Chem 273 (1998) 15418-22.
[106]A.W. Cuthbert, and J.M. Edwardson, Synthesis, properties and biological activity of tritiated N-benzylamidino-3,5-diamino-6-chloro-pyrazine carboxamide--a new ligand for epithelial sodium channels. J Pharm Pharmacol 31 (1979)382-6.
[107]S. Diochot, M. Salinas, A. Baron, P. Escoubas, and M. Lazdunski, Peptides inhibitors of acid-sensing ion channels. Toxicon 49 (2007 February) 271-284
[108]G.R. Dube, S.G Lehto, N.M. Breese, S.J. Baker, X. Wang, M.A. Matulenko, P. Honore, A.O. Stewart, R.B. Moreland, and J.D. Brioni, Electrophysiological and in vivo characterization of A-317567, a novel blocker of acid sensing ion channels. Pain 117 (2005) 88-96.
[109]P. Escoubas, J.R. De Weille, A. Lecoq, S. Diochot, R. Waldmann, G. Champigny, D. Moinier, A. Menez, and M. Lazdunski, Isolation of a Tarantula Toxin Specific for a Class of Proton-gated Na+ Channels. J Biol Chem 275 (2000) 25116-25121.
[110]X. Chen, H. Kalbacher, and S. Grunder, The Tarantula Toxin Psalmotoxin 1 Inhibits Acid-sensing Ion Channel (ASIC) la by Increasing Its Apparent H+ Affinity J Gen Physiol 126 (2005) 71-79.
[111]M. Salinas, L. D. Rash, A. Baron, G. Lambeau, P. Escoubas, and M. Lazdunski, The receptor site of the spider toxin PcTxl on the proton-gated cation channel ASIC1a. J Physiol 570 (2006) 339-354
[112]S. Diochot, A. Baron, L.D. Rash, E. Deval, P. Escoubas, S. Scarzello, M. Salinas, and M. Lazdunski, A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons. EMBO J 23 (2004)1516-25.
[113]B. Chagot, P. Escoubas, S. Diochot, C. Bernard, M. Lazdunski, and H. Darbon, Solution structure of APETx2, a specific peptide inhibitor of ASIC3 proton-gated channels. Protein Sci 14 (2005) 2003-10.
[114]D. Immke, and E. McCleskey, ASIC3:A Lactic Acid Sensor for Cardiac Pain. ScientificWorldJournal 1 (2001) 510-2.
[115]M.P. Price, S.L. McUlwrath, J. Xie, C. Cheng, J. Qiao, D.E. Tarr, K.A. Sluka, T.J. Brennan, G.R. Lewin, and M.J. Welsh, The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice. Neuron 32 (2001) 1071-83.
[116]G. Tombaugh, and R. Sapolsky, Evolving concepts about the role of acidosis in ischemic neuropathology. J Neurochem 61 (1993) 793-803.
[117]Bolshakov KV, Essin KV, Buldakova SL, Dorofeeva NA, Skatchkov SN, Eaton MJ, Tikhonov DB, and M. LG, Characterization of acid-sensitive ion channels in freshly isolated rat brain neurons Neuroscience 110 (2002) 723-730.
[118]E. Tanaka, S. Yasumoto, G. Hattori, S. Niiyama, S. Matsuyama, and H. Higashi, Mechanisms underlying the depression of evoked fast EPSCs following in vitro ischemia in rat hippocampal CA1 neurons. J Neurophysiol 86 (2001) 1095-103.
[119]D. Centonze, E. Saulle, A. Pisani, G. Bernardi, and P. Calabresi, Adenosine-mediated inhibition of striatal GABAergic synaptic transmission during in vitro ischaemia. Brain 124 (2001) 1855-65.
[120]M. Pasternack, S. Smirnov, and K. Kaila, Proton Modulation of Functionally Distinct GABAA Receptors in Acutely Isolated Pyramidal Neurons of Rat Hippocampus. Neuropharmacology 35 (1996) 1279-88.
[121]B.P. Delisle, and J. Satin, pH Modification of Human T-Type Calcium Channel Gating. Biophys J 78 (2000) 1895-1905.
[122]B.K. Siesjo, Acidosis and ischemic brain damage. Neurochem Pathol 9 (1988)31-88.
[123]S. Rehncrona, E. Westerberg, B. Akesson, and B.K. Siesjo, Brain cortical fatty acids and phospholipids during and following complete and severe incomplete ischemia. J Neurochem 38 (1982) 84-93.
[124]M. Johnson, K. Jin, M. Minami, D. Chen, and R.P. Simon, Global ischemia induces expression of acid-sensing ion channel 2a in rat brain. J Cereb Blood Flow Metab 21 (2001) 734-40.
[125]A. Baron, L. Schaefer, E. Lingueglia, G. Champigny, and M. Lazdunski, Zn2+ and H+ Are Coactivators of Acid-sensing Ion Channels. J Biol Chem 276 (2001) 35361-35367.
[126]C.-C. Kuo, and S. Yang, Recovery from Inactivation of T-Type Ca2+ Channels in Rat Thalamic Neurons. J Neurosci 21 (2001) 1884-1892.
[127]P. Zhang, F.J. Sigworth, and C.M. Canessa, Gating of Acid-sensitive Ion Channel-1:Release of Ca2+ Block vs. Allosteric Mechanism JGP,127 (2006)109-117.
[128]K. Katsura, A. Ekholm, B. Asplund, and B.K. Siesjo, Extracellular pH in the brain during ischemia:relationship to the severity of lactic acidosis. J Cereb Blood Flow Metab 11 (1991) 597-9.
[129]R.F. Irvine, How is the level of free arachidonic acid controlled in mammalian cells? Biochem J 204 (1982) 3-16.
[130]A. Marmarou, Intracellular acidosis in human and experimental brain injury. J Neurotrauma 9 (1992) 551-62.
[131]喻卓,and周兰清,膜片钳技术及其在心血管研究中的应用.中国心脏起搏与心电生理杂志14(2000)128-130.
[132]熊巧婕,葛少宇,and何水金,铅对大鼠海马神经细胞H-电流特性的影响.生物物理学报18(2006)197-200.
[133]H.L. Picken Bahrey, and W.J. Moody, Early Development of Voltage-Gated Ion Currents and Firing Properties in Neurons of the Mouse Cerebral Cortex. J. Neurophysiol 89 (2003) 1761-1773.
[134]R. Corlew, M.M. Bosma, and W.J. Moody, Spontaneous, synchronous electrical activity in neonatal mouse cortical neurones. The Journal of Physiology 560 (2004) 377-390.
[135]尹艳玲,李菁锦,and吕国蔚,缺血缺氧对神经细胞突触后电流的影响
及其作用机制.；：.国外医学·生理、病理科学与临床分册23(2003)510-512.
[136]R.G Giffard, H. Monyer, C.W. Christine, and D.W. Choi, Acidosis reduces NMDA receptor activation, glutamate neurotoxicity, and oxygen-glucose deprivation neuronal injury in cortical cultures. Brain Res 506 (1990) 339-42.
[137]D. Li, Z. Shao, T.L. Vanden Hoek, and J.R. Brorson, Reperfusion accelerates acute neuronal death induced by simulated ischemia. Exp Neurol 206 (2007) 280-287.
[138]M. Nedergaard, R.P. Kraig, J. Tanabe, and W.A. Pulsinelli, Dynamics of interstitial and intracellular pH in evolving brain infarct. Am J Physiol Regul Integr Comp Physiol 260 (1991) 581-588.
[139]T. Back, M. Hoehn, G Mies, E. Busch, B. Schmitz, K. Kohno, and K. Hossmann, Penumbral tissue alkalosis in focal cerebral ischemia: relationship to energy metabolism, blood flow, and steady potential Ann Neurol 47 (2000) 485-92.
[140]F.H. Tomlinson, R.E. Anderson, and F.B. Meyer, Brain pHi, cerebral blood flow, and NADH fluorescence during severe incomplete global ischemia in rabbits. Stroke 24 (1993) 435-43.
[141]R. Almaas, M. Pytte, J.K. Lindstad, M. Wright, O.D. Saugstad, D. Pleasure, and T. Rootwelt, Acidosis has opposite effects on neuronal survival during hypoxia and reoxygenation. J Neurochem 84 (2003)1018-27.
[142]Y. Kamada, K. Hiramatsu, and T. Sakaki, Effects of acidosis on the post-hypoxic recovery of synaptic transmission in gerbil hippocampal slices. Brain Res 868 (2000) 347-351.
[143]E. Froyland, F. Wibrand, R. Almaas, I. Dalen, J.K. Lindstad, and T. Rootwelt, Acidosis during Reoxygenation Has an Early Detrimental Effect on Neuronal Metabolic Activity. Pediatr Res 57 (2005) 488-493.
[144]T. Cronberg, A. Rytter, F. Asztely, A. Soder, and T. Wieloch, Glucose but Not Lactate in Combination With Acidosis Aggravates Ischemic Neuronal Death In Vitro. Stroke 35 (2004) 753-757.
[145]L. Chen, Q. Chai, A. Zhao, and X. Chai, Effect of puerarin on cerebral blood flow in dogs. Zhongguo Zhong Yao Za Zhi 20 (1995) 560-562.
[146]王世军,姬广臣,史仁华,李心沁,张栋,and简隆磊,葛根素、川芎嗪、丹参注射液对大脑中动脉阻断大鼠脑微循环血流量的影响中成药22(2000)426-428.
[147]X.H. Xu, and X.X. Zheng, Potential involvement of calcium and nitric oxide in protective effects of puerarin on oxygen-glucose deprivation in cultured hippocampal neurons. J Ethnopharmacol 113 (2007) 421-426
[148]X. Xu, X. Zheng, Q. Zhou, and H. Li, Inhibition of excitatory amino acid efflux contributes to protective effects of puerarin against cerebral ischemia in rats. Biomed Environ Sci 20 (2007) 336-42.
[149]X. Xu, S. Zhang, L. Zhang, W. Yan, and X. Zheng, The Neuroprotection of Puerarin Against Cerebral Ischemia is Associated with the Prevention of Apoptosis in Rats. Planta Med 71 (2005) 585-591.
[150]Guo XG, Chen JZ, Zhang X, and X. Q., Effect of puerarin on L-type calcium channel in isolated rat ventricular myocytes. Zhongguo Zhong Yao Za Zhi.29 (2004) 248-51.
[151]Zhang GQ, Hao XM, Dai DZ, Fu Y, Zhou PA, and W. CH., Puerarin blocks Na+ current in rat ventricular myocytes. Acta Pharmacol Sin.24 (2003) 1212-6.
[152]GQ. Zhang, X.M. Hao, Zhou Pei Ai, C.H. Wu, and D.Z. Dai, Puerarin blocks transient outward K+ current and delayed rectifier K+ current in mice hippocampal CA1 neurons. Acta Pharmacol Sin 22 (2001) 253-6.
[153]X.H. Sun, J.P. Ding, H. Li, N.-Pan, L. Gan, X.L. Yang, and H.B. Xu, Activation of Large-Conductance Calcium-Activated Potassium Channels by Puerarin:The Underlying Mechanism of Puerarin-Mediated Vasodilation. The Journal of Pharmacology and Experimental Therapeutics 323 (2007) 391-397.
[154]Y. Tan, M. Liu, and B. Wu, Puerarin for Acute Ischemic Stroke. Stroke (2008) STROKEAHA.107.512228.
[155]Y. Gao, S.S. Liu, S. Qiu, W. Cheng, J. Zheng, and J.H. Luo, Fluorescence resonance energy transfer analysis of subunit assembly of the ASIC channel. Biochem Biophys Res Commun 359 (2007) 143-50.
[156]Y. Yang, K. Fukui, T. Koike, and X.X. Zheng, Induction of autophagy in neurite degeneration of mouse superior cervical ganglion neurons. Eur J Neurosci 26 (2007) 2979-2988.
[157]Y. Tan, M. Liu, and B. Wu, Puerarin for acute ischaemic stroke. Cochrane Database Syst Rev 1 (2008) CD004955.
[158]H.M. Back T, Mies Q Busch E, Schmitz B, Kohno K, Hossmann KA., Penumbral tissue alkalosis in focal cerebral ischemia:relationship to energy metabolism, blood flow, and steady potential Ann Neurol 47 (2000) 485-92.
[159]徐菊根,葛根素注射液的不良反应及相关因素分析的研究.中国现代药物应用3(2009)21-22.
[160]覃开羽,and吴敏,葛根素的药理作用及不良反应分析.中国药业16(2007)60-61.
[161]D.S.K. Samways, A.B. Harkins, and T.M. Egan, Native and recombinant ASIC1a receptors conduct negligible Ca2+ entry. Cell Calcium 45 (2009) 319-325.
[2]王维治,神经病学,人民卫生出版社,2006.
[3]B.K. Siesjo, K. Katsura, and T. Kristian, Acidosis-related damage. Adv Neurol 71(1996) 209-33; discussion 234-6.
[4]B. Siesjo, Acidosis and ischemic brain damage. Neurochem Pathol 9 (1998) 31-88.
[5]Z.G. Xiong, X.M. Zhu, X.P. Chu, M. Minami, J. Hey, W.L. Wei, J.F. MacDonald, J.A. Wemmie, M.P. Price, M.J. Welsh, and R.P. Simon, Neuroprotection in ischemia:blocking calcium-permeable acid-sensing ion channels. Cell 118 (2004) 687-698.
[6]O. Yermolaieva, A.S. Leonard, M.K. Schnizler, F.M. Abboud, and M.J. Welsh, Extracellular acidosis increases neuronal cell calcium by activating acid-sensing ion channel la. Proc Natl Acad Sci U S A 101 (2004) 6752-7.
[7]贾建平,神经病学,北京大学医学出版社,2004.
[8]杨渊,and张苏明,脑缺血的病理生理研究进展：半暗带、基因表达与神经元保护.国外医学(物理医学与康复学分册)23(2003).
[9]U. Dirnagl, C. Iadecola, and M.A. Moskowitz, Pathobiology of ischaemic stroke:an integrated view. Trends Neurosci 22 (1999) 391-7.
[10]B. Siesjo, Pachophysiology and treatment forcal cerebral ischemia. Part Ⅱ: Mechanisms of damage and treatment.. J Neurosurg 77 (1992) 337-54.
[11]L. Hertz, Bioenergetics of cerebral ischemia:A cellular perspective. Neuropharmacology 55 (2008) 289-309.
[12]J.M. Pocock, and D.G. Nicholls, Exocytotic and nonexocytotic modes of glutamate release from cultured cerebellar granule cells during chemical ischaemia. J Neurochem 70 (1998) 806-13.
[13]D.J. Rossi, T. Oshima, and D. Attwell, Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 403 (2000) 316-21.
[14]R.L. Macdonald, and M. Stoodley, Pathophysiology of cerebral ischemia. Neurol Med Chir (Tokyo) 38 (1998) 1-11.
[15]P. Lipton, Ischemic Cell Death in Brain Neurons. Physiol Rev 79 (1999) 1431-568.
[16]A. Mitani, S. Takeyasu, H. Yanase, Y. Nakamura, and K. Kataoka, Changes in intracellular Ca2+ and energy levels during in vitro ischemia in the gerbil hippocampal slice. J Neurochem 62 (1994) 626-34.
[17]D.J. McConkey, and S. Orrenius, The role of calcium in the regulation of apoptosis. Biochem Biophys Res Commun 239 (1997) 357-66.
[18]A. Diarra, C. Sheldon, C.L. Brett, K.G. Baimbridge, and J. Church, Anoxia-evoked intracellular pH and Ca2+ concentration changes in cultured postnatal rat hippocampal neurons. Neuroscience 93 (1999) 1003-16.
[19]H.A. Kontos, Oxygen radicals in cerebral ischemia:the 2001 Willis lecture. Stroke 32 (2001) 2712-6.
[20]G.H. Danton, and W.D. Dietrich, Inflammatory mechanisms after ischemia and stroke. J Neuropathol Exp Neurol 62 (2003) 127-36.
[21]G.Y. Yang, G.P. Schielke, C. Gong, Y. Mao, H.L. Ge, X.H. Liu, and A.L. Betz, Expression of tumor necrosis factor-alpha and intercellular adhesion molecule-1 after focal cerebral ischemia in interleukin-lbeta converting enzyme deficient mice. J Cereb Blood Flow Metab 19 (1999) 1109-17.
[22]G. Cao, M. Minami, W. Pei, C. Yan, D. Chen, C. O'Horo, S.H. Graham, and J. Chen, Intracellular Bax translocation after transient cerebral ischemia: implications for a role of the mitochondrial apoptotic signaling pathway in ischemic neuronal death. J Cereb Blood Flow Metab 21 (2001) 321-33.
[23]L.L. Dugan, S.L. Sensi, L.M. Canzoniero, S.D. Handran, S.M. Rothman, T.S. Lin, M.P. Goldberg, and D.W. Choi, Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-D-aspartate. J Neurosci 15 (1995) 6377-88.
[24]N. Vila, J. Castillo, A. Davalos, and A. Chamorro, Proinflammatory cytokines and early neurological worsening in ischemic stroke. Stroke 31 (2000) 2325-9.
[25]王军,大鼠脑缺血模型研究进展.中医研究 15(2002)60-62.
[26]O.A. Kryshtal, and V.I. Pidoplichko, Proton receptor in a nerve cell membrane. Dokl Akad Nauk SSSR 255 (1980) 1494-6.
[27]E.Z. Longa, P.R. Weinstein, S. Carlson, and R. Cummins, Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20 (1989) 84-91.
[28]M.P. Goldberg, H. Monyer, J.H. Weiss, and D.W. Choi, Adenosine reduces cortical neuronal injury induced by oxygen or glucose deprivation in vitro. Neurosci Lett 89 (1988) 323-7.
[29]翁骏,and吕秋军,药物代谢稳定性筛选的研究进展.国外医学(药学分册)33(2006)211-214.
[30]杜冠华,高通量药物筛选技术进展与新药开发策略 中国新药杂志 11(2002)31-36.
[31]M. Chesler, The regulation and modulation of pH in the nervous system. Prog Neurobiol 34 (1990) 401-27.
[32]S. Rehncrona, Brain acidosis. Ann Emerg Med 14 (1985) 770-6.
[33]R. Waldmann, G. Champigny, F. Bassilana, C. Heurteaux, and M. Lazdunski, A proton-gated cation channel involved in acid-sensing. Nature 386 (1997) 173-177.
[34]C.C. Chen, S. England, A.N. Akopian, and J.N. Wood, A sensory neuron-specific, proton-gated ion channel. Proc Natl Acad Sci U S A 95 (1998) 10240-10245.
[35]J.A. Saugstad, J.A. Roberts, J. Dong, S. Zeitouni, and R.J. Evans, Analysis of the Membrane Topology of the Acid-sensing Ion Channel 2a. J Biol Chem 279(2004)55514-55519.
[36]R. Waldmann, and M. Lazdunski, H(+)-gated cation channels:neuronal acid sensors in the NaC/DEG family of ion channels. Curr. Opin. Neurobiol.8 (1998)418-24.
[37]D.A. de la Rosa, C.M. Canessa, G.K. Fyfe, and P. Zhang, Structure and Regulation of Amiloride-Sensitive Sodium Channels. Annu Rev Physiol 62 (2000) 573-594.
[38]B.K. Berdiev, T.B. Mapstone, J.M. Markert, Y. Gillespie, J. Lockhart, C.M. Fuller, and D.J. Benos, pH Alterations "Reset" Ca2+ Sensitivity of Brain Na+ Channel 2, a Degenerin/Epithelial Na+ Ion Channel, in Planar Lipid Bilayers. Journal of Biological Chemistry 276 (2001) 38755-38761.
[39]E. Babini, M. Paukert, H.-S. Geisler, and S. Grunder, Alternative splicing and interaction with di-and polyvalent cations control the dynamic range of acid-sensing ion channel (ASIC) 1 J. Biol. Chem (2002).
[40]D. Immke, and E. McCleskey, Protons open acid-sensing ion channels by catalyzing relief of Ca2+ blockade. Neuron 37 (2003) 75-84.
[41]J.d. Weille, and F. Bassilana, Dependence of the acid-sensitive ion channel, ASICla, on extracellular Ca2+ ions Brain Research 900 (2001) 277-281
[42]H. Cadiou, M. Studer, N.G. Jones, E.S.J. Smith, A. Ballard, S.B. McMahon, and P.A. McNaughtop, Modulation of Acid-Sensing Ion Channel Activity by Nitric Oxide. J Neurosci 27 (2007) 13251-13260.
[43]J. Gao, B. Duan, D.G. Wang, X.H. Deng, G.Y. Zhang, L. Xu, and T.L. Xu, Coupling between NMDA Receptor and Acid-Sensing Ion Channel Contributes to Ischemic Neuronal Death. Neuron 48 (2005) 635-646.
[44]O. Krishtal, The ASICs:Signaling molecules? Modulators?. Trends in Neurosciences 26 (2003) 477-483
[45]J. Jasti, H. Furukawa, E.B. Gonzales, and E. Gouaux, Structure of acid-sensing ion channel 1 at 1.9A resolution and low pH. Nature 449 (2007)316-323.
[46]Yang H, Yu Y, Li W, Xu T, and J. H, Inherent dynamics of the acid-sensing ion channel 1 correlates with the gating mechanism. PLoS Biol 7 (2009) e1000151.
[47]E. Lingueglia, J.R. de Weille, F. Bassilana, C. Heurteaux, H. Sakai, R. Waldmann,and M. Lazdunski, A Modulatory Subunit of Acid Sensing Ion Channels in Brain and Dorsal Root Ganglion Cells. J. Biol. Chem.272 (1997) 29778-29783.
[48]M. Ettaiche, N. Guy, P. Hofman, M. Lazdunski, and R. Waldmann, Acid-Sensing Ion Channel 2 Is Important for Retinal Function and Protects against Light-Induced Retinal Degeneration. J Neurosci 24 (2004) 1005-1012.
[49]D.A. de la Rosa, S.R. Krueger, A. Kolar, D. Shao, R.M. Fitzsimonds, and C.M. Canessa, Distribution, subcellular localization and ontogeny of ASIC1 in the mammalian central nervous system. J Physiol 546 (2003) 77-87.
[50]J.A. Wemmie, J. Chen, C.C. Askwith, A.M. Hruska-Hageman, M.P. Price, B.C. Nolan, P.G. Yoder, E. Lamani, T. Hoshi, J.H. Freeman, and M.J. Welsh, The Acid-Activated Ion Channel ASIC Contributes to Synaptic Plasticity, Learning, and Memory. Neuron 34 (2002) 463-77.
[51]C. Roza, J.-L. Puel, M. Kress, A. Baron, S. Diochot, M. Lazdunski, and R. Waldmann, Knockout of the ASIC2 channel in mice does not impair cutaneous mechanosensation, visceral mechanonociception and hearing. J Physiol 558 (2004) 659-669
[52]S. Ugawa, Y. Minami, W. Guo, Y. Saishin, K. Takatsuji, T. Yamamoto, M. Tqhyama, and S. Shimada, Receptor that leaves a sour taste in the mouth. Nature 395 (1998) 555-6.
[53]R. Waldmann, F. Bassilana, J. de Weille, G. Champigny, C. Heurteaux, and M. Lazdunski, Molecular Cloning of a Non-inactivating Proton-gated Na+ Channel Specific for Sensory Neurons. J Biol Chem 272 (1997) 20975-20978.
[54]Q.Y. Meng, W. Wang, X.N. Chen, T.L. Xu, and J.N. Zhou, Distribution of acid-sensing ion channel 3 in the rat hypothalamus. Neurosci 159 (2009) 1126-1134.
[55]S.P. Sutherland, C.J. Benson, J.P. Adelman, and E.W. McCleskey, Acid-sensing ion channel 3 matches the acid-gated current in cardiac ischemia-sensing neurons,2001, pp.711-716.
[56]A.N. Akopian, C.-C. Chen, Y. Ding, P. Cesare, and J.N. Wood, A new member of the acid-sensing ion channel family. Neuroreport 11 (2000) 2217-22.
[57]S. Grander, H.-S. Geissler, E.-L. Bessler, and J.P. Ruppersberg, A new member of acid-sensing ion channels from pituitary gland. NeuroReport 11(2000)1607-1611.
[58]伍龙军,and徐天乐,酸敏感离子通道研究进展.生物化学与生物物理进展29(2002)197-203.
[59]C. Askwith, J. Wemmie, M. Price, T. Rokhlina, and M. Welsh, Acid-sensing ion channel 2 (ASIC2) modulates ASIC1 H+-activated currents in hippocampal neurons. J Biol Chem 279 (2004) 18296-305.
[60]A. Baron, R. Waldmann, and M. Lazdunski, ASIC-like, proton-activated currents in rat hippocampal neurons. J Physiol 539 (2002) 485-494.
[61]B.K. Berdiev, J. Xia, L.A. McLean, J.M. Markert, G.Y. Gillespie, T.B. Mapstone, A.P. Naren, B. Jovov, J.K. Bubien, H.-L. Ji, C.M. Fuller, K.L Kirk, and D.J. Benos, Acid-sensing Ion Channels in Malignant Gliomas J. Biol. Chem.278 (2003) 15023-15034.
[62]J.-H. Yea, J. Gaoc, Y.-N. Wub, Y.-J. Hua, C.-P. Zhanga, and T.-L. Xu, Identification of acid-sensing ion channels in adenoid cystic carcinomas. Biochem Biophys Res Commun 355 (2007 April 20) 986-992
[63]X. Su, Q. Li, K. Shrestha, E. Cormet-Boyaka, L. Chen, P.R. Smith, E.J. Sorscher, D.J. Benos, S. Matalon, and H.-L. Ji, Interregulation of Proton-gated Na+ Channel 3 and Cystic Fibrosis Transmembrane Conductance Regulator. J Biol Chem 281 (2006) 36960-36968.
[64]袁凤来,陈飞虎,李霞,黄学应,吴繁荣,张腾跃,吕元庆,and李俊,重组人内抑素对佐剂性关节炎大鼠关节软骨酸敏感离子通道的影响及其保护作用 中国药理学通报 24(2008)893-897.
[65]袁凤来,陈飞虎,黄学应,李霞,吴繁荣,阮晶晶,and李俊,酸敏感离子通道在大鼠佐剂性关节炎关节软骨中的表达 中华风湿病学杂志12(2008)321-325.
[66]P.W. Reeh, and M. Kress, Molecular physiology of proton transduction in nociceptors. Curr Opin Pharmacol 1 (2001)45-51.
[67]M. Ettaiche, E. Deval, M. Cougnon, M. Lazdunski, and N. Voilley, Silencing Acid-Sensing Ion Channel 1a Alters Cone-Mediated Retinal Function. J Neurosci 26 (2006) 5800-5809.
[68]M. Driscoll, and M. Chalfie, The mec-4 gene is a member of a family of Caenorhabditis elegans genes that can mutate to induce neuronal degeneration. Nature 349 (1991) 588-93.
[69]M.P. Price, GR. Lewin, S.L. Mcllwrath, C. Cheng, J. Xie, P.A. Heppenstall, C.L. Stucky, A.G. Mannsfeldt, T.J. Brennan, H.A. Drummond, J. Qiao, C.J. Benson, D.E. Tarr, R.F. Hrstka, B. Yang, R.A. Williamson, and M.J. Welsh, The mammalian sodium channel BNC1 is required for normal touch sensation. Nature 407 (2000) 1007-11.
[70]L. Liu, and S.A. Simon, Acidic stimuli activates two distinct pathways in taste receptor cells from rat fungiform papillae. Brain Res 923 (2001) 58-70.
[71]J.G. Brand, Cloning and expression of an ASIC1 from human taste tissue. in: K. Persaud, and S. Van Toller, (Eds.), International Symposium on Olfaction and Taste, European Chemoreception Research Organisation, Brighton, UK,2000, pp.80.
[72]W. Lennox, The effect on epileptic seizures of varying the composition of the respired air. J Clin Invest 4 (1929) 23-24.
[73]L. Velisek, J. Dreier, P. Stanton, U. Heinemann, and S. Moshe, Lowering of extracellular pH suppresses low-Mg2+-induced seizures in combined entorhinal cortex-hiipocampal slices. Exp. Brain Res 101 (1994) 44-52.
[74]A.E. Ziemann, M.K. Schnizler, G.W. Albert, M.A. Severson, M.A. Howard Iii, M.J. Welsh, and J.A. Wemmie, Seizure termination by acidosis depends on ASIC1a. Nat Neurosci 11 (2008) 816-822.
[75]Z.Q. Xiong, and J.L. Stringer, Extracellular pH responses in CA1 and the dentate gyrus during electrical stimulation, seizure discharges, and spreading depression. J Neurophysiol 83 (2000) 3519-24.
[76]G. Biaginib, K. Babinskid, M. Avoli, M. Marcinkiewicz, and P. Seguela, Regional and Subunit-Specific Downregulation of Acid-Sensing Ion Channels in the Pilocarpine Model of Epilepsy Neurobiology of Disease 8 (2001) 45-48.
[77]N.G. Prosper, Amiloride delays the onset of pilocarpine-induced seizures in rats. Brain Research 1222 (2008) 230-232.
[78]M.B. Graebera, and U. Miillerb, Recent developments in the molecular genetics of mitochondrial disorders J Neurol Sci 153 (1998)251-63.
[79]A. Bender, K. Krishnan, C. Morris, G. Taylor, A. Reeve, R. Perry, E. Jaros, J. Hersheson, J. Betts, T. Klopstock, R. Taylor, and D. Turnbull, High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson's disease. Nat. Genet 38 (2006) 515-517.
[80]S.E. Browne, and M.F. Beal, The energetics of Huntington's disease. Neurochem Res 29 (2004) 531-546.
[81]M.A. Friese, M.J. Crane, R. Etzensperger, S. Vergo, J.A. Wemmie, M.J. Welsh, A. Vincent, and L. Fugge, Acid-sensing ion channel-1 contributes to axonal degeneration in autoimmune inflammation of the central nervous system. Nature Medicine 13 (2007) 1483-1489
[82]R.L. Arias, M.L. Sung, D. Vasylyev, M.Y. Zhang, K. Albinson, K. Kubek, N. Kagan, C. Beyer, Q. Lin, J.M. Dwyer, M.M. Zaleska, M.R. Bowlby, J. Dunlop, and M. Monaghan, Amiloride is neuroprotective in an MPTP model of Parkinson's disease. Neurobiol Dis 31 (2008) 334-41.
[83]H. Wong, P. Bauer, M. Kurosawa, A. Goswami, C. Washizu, Y. Machida, A. Tosaki, M. Yamada, T. Knopfel, T. Nakamura, and N. Nukina, Blocking acid-sensing ion channel 1 alleviates Huntington's disease pathology via an ubiquitin-proteasome system-dependent mechanism. Hum Mol Genet 17(2008)3223-35.
[84]D.C. Immke, and E.W. McCleskey, Lactate enhances the acid-sensing Na+ channel on ischemia-sensing neurons. Nat Neurosci 4 (2001) 869-870.
[85]N. Voilley, J. de Weille, J. Mamet, and M. Lazdunski, Nonsteroid Anti-Inflammatory Drugs Inhibit Both the Activity and the Inflammation-Induced Expression of Acid-Sensing Ion Channels in Nociceptors. J Neurosci 21 (2001) 8026-8033.
[86]J. Mamet, A. Baron, M. Lazdunski, and N. Voilley, ProInflammatory Mediators, Stimulators of Sensory Neuron Excitability via the Expression of Acid-Sensing Ion Channels. J Neurosci 22 (2002) 10662-10670.
[87]G. Pignataro, R.P. Simon, and Z.G. Xiong, Prolonged activation of ASIC1a and the time window for neuroprotection in cerebral ischemia. Brain 130 (2007) 151-158.
[88]Z.G. Xiong, G. Pignataro, M. Li, S. Chang, and R.P. Simon, Acid-sensing ion channels (ASICs) as pharmacological targets for neurodegenerative diseases Curr Opin Pharmacol 8 (2008)25-32.
[89]J.S. Mogil, N.M. Breese, M.-F. Witty, J. Ritchie, M.-L. Rainville, A. Ase, N. Abbadi, C.L. Stucky, and P. Seguela, Transgenic Expression of a Dominant-Negative ASIC3 Subunit Leads to Increased Sensitivity to Mechanical and Inflammatory Stimuli. J Neurosci 25 (2005) 9893-9901.
[90]E. Deval, J. Noel, N. Lay, A. Alloui, S. Diochot, V. Friend, M. Jodar, M. Lazdunski, and E. Lingueglia, ASIC3, a sensor of acidic and primary inflammatory pain. EMBO J 27 (2008) 3047-55.
[91]M. Mazzuca, C. Heurteaux, A. Alloui, S. Diochot, A. Baron, N. Voilley, N. Blondeau, P. Escoubas, A. Gelot, A. Cupo, A. Zimmer, A.M. Zimmer, A. Eschalier, and M. Lazdunski, A tarantula peptide against pain via ASIC1a channels and opioid mechanisms. Nat Neurosci 10 (2007) 943-945.
[92]B. Duan, L.-J. Wu, Y.-Q. Yu, Y. Ding, L. Jing, L. Xu, J. Chen, and T.-L. Xu, Upregulation of Acid-Sensing Ion Channel ASIC1a in Spinal Dorsal Horn Neurons Contributes to Inflammatory Pain Hypersensitivity. J Neurosci 27 (2007)11139-11148.
[93]A.A. Staniland, and S.B. McMahon, Mice lacking acid-sensing ion channels (ASIC) 1 or 2, but not ASIC3, show increased pain behaviour in the formalin test. EurJ Pain 13 (2009) 554-563
[94]S. Gregoire, and J. Matricon, Differential Involvement of ASIC1a in the Basolateral Amygdala in Fear Memory and Unconditioned Fear Responses. J. Neurosci 29 (2009) 6053-6054.
[95]M.W. Coryell, A.M. Wunsch, J.M. Haenfler, J.E. Allen, J.L. McBride, B.L. Davidson, and J.A. Wemmie, Restoring Acid-Sensing Ion Channel-la in the Amygdala of Knock-Out Mice Rescues Fear Memory But Not Unconditioned Fear Responses. J Neurosci 28 (2008) 13738-13741.
[96]M.W. Coryell, A.E. Ziemann, P.J. Westmoreland, J.M. Haenfler, Z. Kurjakovic, X.M. Zha, M. Price, M.K. Schnizler, and J.A. Wemmie, Targeting ASIC1a Reduces Innate Fear and Alters Neuronal Activity in the Fear Circuit. Biol Psychiatry 62 (2007) 1140-1148.
[97]J.A. Wemmie, M.W. Coryell, C.C. Askwith, E. Lamani, A.S. Leonard, C.D. Sigmund, and M.J. Welsh, Overexpression of acid-sensing ion channel la in transgenic mice increases acquired fear-related behavior.101 (2004) 3621-3626.
[98]M.W. Coryell, A.M.Wunsch,J.M. Haenfler, J.E. Allen, M. Schnizler, A.E. Ziemann, M.N. Cook, J.P. Dunning, M.P. Price, J.D. Rainier, Z. Liu, A.R. Light, D.R. Langbehn, and J.A. Wemmie, Acid-Sensing Ion Channel-1a in the Amygdala, a Novel Therapeutic Target in Depression-Related Behavior. J. Neurosci 29 (2009) 5381-5388.
[99]T.R. Kleyman, and E.J. Cragoe, Jr., Amiloride and its analogs as tools in the study of ion transport. J Membr Biol 105 (1988) 1-21.
[100]S. Attaphitaya, K. Park, and J.E. Melvin, Molecular Cloning and Functional Expression of a Rat Na+/H+ Exchanger (NHE5) Highly Expressed in Brain. J Biol Chem 274 (1999) 4383-4388.
[101]R. Waldmann, G. Champigny, N. Voilley, I. Lauritzen, and M. Lazdunski, The Mammalian Degenerin MDEG, an Amiloride-sensitive Cation Channel Activated by Mutations Causing Neurodegeneration in Caenorhabditis elegans. J Biol Chem 271 (1996) 10433-10436.
[102]M. Vukicevic, and S. Kellenberger, Modulatory effects of acid-sensing ion channels on action potential generation in hippocampal neurons. AM J Physiol-CELL PH 287 (2004) 682-690.
[103]Wu LJ, Duan B, Mei YD, Gao J, Chen JQ Zhuo M, Xu L, Wu M, and X. TL, Characterization of acid-sensing ion channels in dorsal horn neurons of rat spinal cord. J Biol Chem 279 (2004) 43716-43724.
[104]L. Schild, E. Schneeberger, I. Gautschi, and D. Firsov, Identification of amino acid residues in the alpha, beta, and gamma subunits of the epithelial sodium channel (ENaC) involved in amiloride block and ion permeation. J Gen Physiol 109 (1997) 15-26.
[105]G. Champigny, N. Voilley, R. Waldmann, and M. Lazdunski, Mutations causing neurodegeneration in Caenorhabditis elegans drastically alter the pH sensitivity and inactivation of the mammalian H+-gated Na+ channel MDEG1.J Biol Chem 273 (1998) 15418-22.
[106]A.W. Cuthbert, and J.M. Edwardson, Synthesis, properties and biological activity of tritiated N-benzylamidino-3,5-diamino-6-chloro-pyrazine carboxamide--a new ligand for epithelial sodium channels. J Pharm Pharmacol 31 (1979)382-6.
[107]S. Diochot, M. Salinas, A. Baron, P. Escoubas, and M. Lazdunski, Peptides inhibitors of acid-sensing ion channels. Toxicon 49 (2007 February) 271-284
[108]G.R. Dube, S.G Lehto, N.M. Breese, S.J. Baker, X. Wang, M.A. Matulenko, P. Honore, A.O. Stewart, R.B. Moreland, and J.D. Brioni, Electrophysiological and in vivo characterization of A-317567, a novel blocker of acid sensing ion channels. Pain 117 (2005) 88-96.
[109]P. Escoubas, J.R. De Weille, A. Lecoq, S. Diochot, R. Waldmann, G. Champigny, D. Moinier, A. Menez, and M. Lazdunski, Isolation of a Tarantula Toxin Specific for a Class of Proton-gated Na+ Channels. J Biol Chem 275 (2000) 25116-25121.
[110]X. Chen, H. Kalbacher, and S. Grunder, The Tarantula Toxin Psalmotoxin 1 Inhibits Acid-sensing Ion Channel (ASIC) la by Increasing Its Apparent H+ Affinity J Gen Physiol 126 (2005) 71-79.
[111]M. Salinas, L. D. Rash, A. Baron, G. Lambeau, P. Escoubas, and M. Lazdunski, The receptor site of the spider toxin PcTxl on the proton-gated cation channel ASIC1a. J Physiol 570 (2006) 339-354
[112]S. Diochot, A. Baron, L.D. Rash, E. Deval, P. Escoubas, S. Scarzello, M. Salinas, and M. Lazdunski, A new sea anemone peptide, APETx2, inhibits ASIC3, a major acid-sensitive channel in sensory neurons. EMBO J 23 (2004)1516-25.
[113]B. Chagot, P. Escoubas, S. Diochot, C. Bernard, M. Lazdunski, and H. Darbon, Solution structure of APETx2, a specific peptide inhibitor of ASIC3 proton-gated channels. Protein Sci 14 (2005) 2003-10.
[114]D. Immke, and E. McCleskey, ASIC3:A Lactic Acid Sensor for Cardiac Pain. ScientificWorldJournal 1 (2001) 510-2.
[115]M.P. Price, S.L. McUlwrath, J. Xie, C. Cheng, J. Qiao, D.E. Tarr, K.A. Sluka, T.J. Brennan, G.R. Lewin, and M.J. Welsh, The DRASIC cation channel contributes to the detection of cutaneous touch and acid stimuli in mice. Neuron 32 (2001) 1071-83.
[116]G. Tombaugh, and R. Sapolsky, Evolving concepts about the role of acidosis in ischemic neuropathology. J Neurochem 61 (1993) 793-803.
[117]Bolshakov KV, Essin KV, Buldakova SL, Dorofeeva NA, Skatchkov SN, Eaton MJ, Tikhonov DB, and M. LG, Characterization of acid-sensitive ion channels in freshly isolated rat brain neurons Neuroscience 110 (2002) 723-730.
[118]E. Tanaka, S. Yasumoto, G. Hattori, S. Niiyama, S. Matsuyama, and H. Higashi, Mechanisms underlying the depression of evoked fast EPSCs following in vitro ischemia in rat hippocampal CA1 neurons. J Neurophysiol 86 (2001) 1095-103.
[119]D. Centonze, E. Saulle, A. Pisani, G. Bernardi, and P. Calabresi, Adenosine-mediated inhibition of striatal GABAergic synaptic transmission during in vitro ischaemia. Brain 124 (2001) 1855-65.
[120]M. Pasternack, S. Smirnov, and K. Kaila, Proton Modulation of Functionally Distinct GABAA Receptors in Acutely Isolated Pyramidal Neurons of Rat Hippocampus. Neuropharmacology 35 (1996) 1279-88.
[121]B.P. Delisle, and J. Satin, pH Modification of Human T-Type Calcium Channel Gating. Biophys J 78 (2000) 1895-1905.
[122]B.K. Siesjo, Acidosis and ischemic brain damage. Neurochem Pathol 9 (1988)31-88.
[123]S. Rehncrona, E. Westerberg, B. Akesson, and B.K. Siesjo, Brain cortical fatty acids and phospholipids during and following complete and severe incomplete ischemia. J Neurochem 38 (1982) 84-93.
[124]M. Johnson, K. Jin, M. Minami, D. Chen, and R.P. Simon, Global ischemia induces expression of acid-sensing ion channel 2a in rat brain. J Cereb Blood Flow Metab 21 (2001) 734-40.
[125]A. Baron, L. Schaefer, E. Lingueglia, G. Champigny, and M. Lazdunski, Zn2+ and H+ Are Coactivators of Acid-sensing Ion Channels. J Biol Chem 276 (2001) 35361-35367.
[126]C.-C. Kuo, and S. Yang, Recovery from Inactivation of T-Type Ca2+ Channels in Rat Thalamic Neurons. J Neurosci 21 (2001) 1884-1892.
[127]P. Zhang, F.J. Sigworth, and C.M. Canessa, Gating of Acid-sensitive Ion Channel-1:Release of Ca2+ Block vs. Allosteric Mechanism JGP,127 (2006)109-117.
[128]K. Katsura, A. Ekholm, B. Asplund, and B.K. Siesjo, Extracellular pH in the brain during ischemia:relationship to the severity of lactic acidosis. J Cereb Blood Flow Metab 11 (1991) 597-9.
[129]R.F. Irvine, How is the level of free arachidonic acid controlled in mammalian cells? Biochem J 204 (1982) 3-16.
[130]A. Marmarou, Intracellular acidosis in human and experimental brain injury. J Neurotrauma 9 (1992) 551-62.
[131]喻卓,and周兰清,膜片钳技术及其在心血管研究中的应用.中国心脏起搏与心电生理杂志14(2000)128-130.
[132]熊巧婕,葛少宇,and何水金,铅对大鼠海马神经细胞H-电流特性的影响.生物物理学报18(2006)197-200.
[133]H.L. Picken Bahrey, and W.J. Moody, Early Development of Voltage-Gated Ion Currents and Firing Properties in Neurons of the Mouse Cerebral Cortex. J. Neurophysiol 89 (2003) 1761-1773.
[134]R. Corlew, M.M. Bosma, and W.J. Moody, Spontaneous, synchronous electrical activity in neonatal mouse cortical neurones. The Journal of Physiology 560 (2004) 377-390.
[135]尹艳玲,李菁锦,and吕国蔚,缺血缺氧对神经细胞突触后电流的影响
及其作用机制.；：.国外医学·生理、病理科学与临床分册23(2003)510-512.
[136]R.G Giffard, H. Monyer, C.W. Christine, and D.W. Choi, Acidosis reduces NMDA receptor activation, glutamate neurotoxicity, and oxygen-glucose deprivation neuronal injury in cortical cultures. Brain Res 506 (1990) 339-42.
[137]D. Li, Z. Shao, T.L. Vanden Hoek, and J.R. Brorson, Reperfusion accelerates acute neuronal death induced by simulated ischemia. Exp Neurol 206 (2007) 280-287.
[138]M. Nedergaard, R.P. Kraig, J. Tanabe, and W.A. Pulsinelli, Dynamics of interstitial and intracellular pH in evolving brain infarct. Am J Physiol Regul Integr Comp Physiol 260 (1991) 581-588.
[139]T. Back, M. Hoehn, G Mies, E. Busch, B. Schmitz, K. Kohno, and K. Hossmann, Penumbral tissue alkalosis in focal cerebral ischemia: relationship to energy metabolism, blood flow, and steady potential Ann Neurol 47 (2000) 485-92.
[140]F.H. Tomlinson, R.E. Anderson, and F.B. Meyer, Brain pHi, cerebral blood flow, and NADH fluorescence during severe incomplete global ischemia in rabbits. Stroke 24 (1993) 435-43.
[141]R. Almaas, M. Pytte, J.K. Lindstad, M. Wright, O.D. Saugstad, D. Pleasure, and T. Rootwelt, Acidosis has opposite effects on neuronal survival during hypoxia and reoxygenation. J Neurochem 84 (2003)1018-27.
[142]Y. Kamada, K. Hiramatsu, and T. Sakaki, Effects of acidosis on the post-hypoxic recovery of synaptic transmission in gerbil hippocampal slices. Brain Res 868 (2000) 347-351.
[143]E. Froyland, F. Wibrand, R. Almaas, I. Dalen, J.K. Lindstad, and T. Rootwelt, Acidosis during Reoxygenation Has an Early Detrimental Effect on Neuronal Metabolic Activity. Pediatr Res 57 (2005) 488-493.
[144]T. Cronberg, A. Rytter, F. Asztely, A. Soder, and T. Wieloch, Glucose but Not Lactate in Combination With Acidosis Aggravates Ischemic Neuronal Death In Vitro. Stroke 35 (2004) 753-757.
[145]L. Chen, Q. Chai, A. Zhao, and X. Chai, Effect of puerarin on cerebral blood flow in dogs. Zhongguo Zhong Yao Za Zhi 20 (1995) 560-562.
[146]王世军,姬广臣,史仁华,李心沁,张栋,and简隆磊,葛根素、川芎嗪、丹参注射液对大脑中动脉阻断大鼠脑微循环血流量的影响中成药22(2000)426-428.
[147]X.H. Xu, and X.X. Zheng, Potential involvement of calcium and nitric oxide in protective effects of puerarin on oxygen-glucose deprivation in cultured hippocampal neurons. J Ethnopharmacol 113 (2007) 421-426
[148]X. Xu, X. Zheng, Q. Zhou, and H. Li, Inhibition of excitatory amino acid efflux contributes to protective effects of puerarin against cerebral ischemia in rats. Biomed Environ Sci 20 (2007) 336-42.
[149]X. Xu, S. Zhang, L. Zhang, W. Yan, and X. Zheng, The Neuroprotection of Puerarin Against Cerebral Ischemia is Associated with the Prevention of Apoptosis in Rats. Planta Med 71 (2005) 585-591.
[150]Guo XG, Chen JZ, Zhang X, and X. Q., Effect of puerarin on L-type calcium channel in isolated rat ventricular myocytes. Zhongguo Zhong Yao Za Zhi.29 (2004) 248-51.
[151]Zhang GQ, Hao XM, Dai DZ, Fu Y, Zhou PA, and W. CH., Puerarin blocks Na+ current in rat ventricular myocytes. Acta Pharmacol Sin.24 (2003) 1212-6.
[152]GQ. Zhang, X.M. Hao, Zhou Pei Ai, C.H. Wu, and D.Z. Dai, Puerarin blocks transient outward K+ current and delayed rectifier K+ current in mice hippocampal CA1 neurons. Acta Pharmacol Sin 22 (2001) 253-6.
[153]X.H. Sun, J.P. Ding, H. Li, N.-Pan, L. Gan, X.L. Yang, and H.B. Xu, Activation of Large-Conductance Calcium-Activated Potassium Channels by Puerarin:The Underlying Mechanism of Puerarin-Mediated Vasodilation. The Journal of Pharmacology and Experimental Therapeutics 323 (2007) 391-397.
[154]Y. Tan, M. Liu, and B. Wu, Puerarin for Acute Ischemic Stroke. Stroke (2008) STROKEAHA.107.512228.
[155]Y. Gao, S.S. Liu, S. Qiu, W. Cheng, J. Zheng, and J.H. Luo, Fluorescence resonance energy transfer analysis of subunit assembly of the ASIC channel. Biochem Biophys Res Commun 359 (2007) 143-50.
[156]Y. Yang, K. Fukui, T. Koike, and X.X. Zheng, Induction of autophagy in neurite degeneration of mouse superior cervical ganglion neurons. Eur J Neurosci 26 (2007) 2979-2988.
[157]Y. Tan, M. Liu, and B. Wu, Puerarin for acute ischaemic stroke. Cochrane Database Syst Rev 1 (2008) CD004955.
[158]H.M. Back T, Mies Q Busch E, Schmitz B, Kohno K, Hossmann KA., Penumbral tissue alkalosis in focal cerebral ischemia:relationship to energy metabolism, blood flow, and steady potential Ann Neurol 47 (2000) 485-92.
[159]徐菊根,葛根素注射液的不良反应及相关因素分析的研究.中国现代药物应用3(2009)21-22.
[160]覃开羽,and吴敏,葛根素的药理作用及不良反应分析.中国药业16(2007)60-61.
[161]D.S.K. Samways, A.B. Harkins, and T.M. Egan, Native and recombinant ASIC1a receptors conduct negligible Ca2+ entry. Cell Calcium 45 (2009) 319-325.