听源性癫痫发作大鼠脑内谷氨酸转运蛋白GLAST表达的变化及NO调控机制的研究
|
摘要
目的：癫痫是一种慢性脑部疾患，其病因及发病机制十分复杂，虽然谷氨酸作为兴奋性神经递质，在癫痫发病中的作用已得到证实，但谷氨酸在突触间隙唯一的清除途径—由谷氨酸转运蛋白介导的重摄取机制与癫痫发作关系的研究还仅仅是开始，国内尚未见报导，一氧化氮作为一个特殊的信速传递分子，在癫痫发病中究竟是参与致痫还是抗痫，亦无定论。且一氧化氮与谷氨酸转运蛋白是否有内在的调控关系亦不清楚。因此，本研究旨在探讨听源性癫痫发作时大鼠脑内谷氨酸转运蛋白GLAST表达的动态变化及L-NNA、L-Arg干预后大鼠癫痫发作的行为学改变及GLAST表达的变化。
方法：实验动物选用P~(77)PMC型GEPRs大鼠(购自北京医科大学实验动物中心)，随机分为对照组及实验组，后者又分为癫痫发作后30min、1h、3h、6h、12h及72h组。听觉诱导癫痫发作采用电铃刺激，刺激时间：60秒，刺激强度：120dB。分别用免疫组织化学ABC法，免疫印迹法(Western blotting)及反转录聚合酶链法(RT-PCR)从细胞及分子水平观察GLAST
Aim: The etiology and pathogenesis of epilepsy, one of the chronic cerebral diseases, were not very clear. Though it was proved that glutamate plays a crucial role in epileptic events, the relationship between epilepsy and the reintake mechanism in the synaptic cleft mediated by glutamate transporter, is still at its primary stage. Furthermore, there is no domestic report concerned with it. There is no definite answer for whether NO, a special molecular messenger, functions as epilepsy inducer or antiepileptic factor. In addition, whether there exists an interregulatory factor between No and excitatory neurotransmitter glutamate also needs further study. This paper is to study the dynamic changes in the expression of intracerebral glutamate transporter GLAST in audiogenic seizure rats. Meanwhile the behavioral changes and changes in expression of GLAST in L-Arg andrg and L-NNA interfered audiogenic seizure rats were also observed.
Methods: The experiment P~(77)PMC CEPRs rats were bought from the Experimental Animal Center of Beijing Medical University. The rats were randomly grouped as the control and the experimental, the latter were grouped as
方法：实验动物选用P~(77)PMC型GEPRs大鼠(购自北京医科大学实验动物中心)，随机分为对照组及实验组，后者又分为癫痫发作后30min、1h、3h、6h、12h及72h组。听觉诱导癫痫发作采用电铃刺激，刺激时间：60秒，刺激强度：120dB。分别用免疫组织化学ABC法，免疫印迹法(Western blotting)及反转录聚合酶链法(RT-PCR)从细胞及分子水平观察GLAST
Aim: The etiology and pathogenesis of epilepsy, one of the chronic cerebral diseases, were not very clear. Though it was proved that glutamate plays a crucial role in epileptic events, the relationship between epilepsy and the reintake mechanism in the synaptic cleft mediated by glutamate transporter, is still at its primary stage. Furthermore, there is no domestic report concerned with it. There is no definite answer for whether NO, a special molecular messenger, functions as epilepsy inducer or antiepileptic factor. In addition, whether there exists an interregulatory factor between No and excitatory neurotransmitter glutamate also needs further study. This paper is to study the dynamic changes in the expression of intracerebral glutamate transporter GLAST in audiogenic seizure rats. Meanwhile the behavioral changes and changes in expression of GLAST in L-Arg andrg and L-NNA interfered audiogenic seizure rats were also observed.
Methods: The experiment P~(77)PMC CEPRs rats were bought from the Experimental Animal Center of Beijing Medical University. The rats were randomly grouped as the control and the experimental, the latter were grouped as
引文
1. Chol DW. Glutamate neurotoxicity and diseases of the system. Neuron, 1988,1:623-634.
2. Coyle JT. Neurotoxic action of kainic acid. J.Neuro-chem, 1983,41:1-11.
3. Coyle JT, Puttfarken P. Oxidative stress, glutamate, and neurodegenerative disorder. Science, 1993,262:689-695.
4. Danbolt NC. The high affinity uptake system for excitatory amino acids in the brain. Prog neurobiol, 1994,44:377-396.
5. Kanai Y, Nussberger S, Romoro MF, et al. Electrogenic properties of the epithelial and neuronal high affinity glutamate transporter. J Biol Chem, 1995,270:16561-16568.
6. Bouvier M, Szatkowski M, Amato A, et al. The glial cell glutamate uptake carrier countertransports PH-changing anions. Nature, 1992,360:471-474.
7. Nicholls D, Attwell D. The release and uptake of excitatory amino acids. TIPS, 1990,11:462-468.
8. Stork T, Schulte S, Hoffman K, et al. Structure, expression and functional analysis of a Na+-dependent glutamate/aspartate transporter from rat brain. Proc. Natl. Acad. Sci, 1992,89:10955-10959.
9. Pines G, Danbolt NC, Bjoras M, et al. Cloning and expression of a rat brain L-glutamate transporter. Nature, 1992,360:461-467.
10. Kanai Y, Hediger MA. Primary structure and functional characterization of a high affinity glutamate transporter. Nature, 1992,360:467-471.
11. Ariza JL, Eliasof S, Kavanaugh MP, ET al. Excitatory amino acid transporter 5, aretinal glutamate transporter coupled to a chloride conductance. Proc. Natl. Acad. Sci, 1997, 94:41-55-4160.
12. Maeno-Hikichi Y, Tanaka K, Shibata T, et al. Structure and functional expression of the cloned mouse neuronal high-affinity glutamate transporter. Brain Res Mol Brain Res. 1997, 48:176-180.
13. Eliasof S, Arriza JL, Leighton BH, et al. Excitatory amino acid transporters of the solamander retina: identification, localization, and function. J Neurosci, 1998, 18:698-712.
14. Inoue K, Sakaitani M, Shimada S, et al. Cloning and expression of a bovine glutamate transporter. Brain Res Mol Brain Res, 1995, 28:343-348.
15．高文，饶志仁。神经递质转运体的研究进展。生理科学进展，1997，28：203-208。
16. Levy LK, Chaudhry FA, Honore T, et al. Brain glutamate transporter proteins from homomultimers. J Biol Chem, 1996, 271:27715-27722.
17. Conradt M, Stoffei W. Functional analysis of the high affinity, Na+-dependent glutamate transporter GLAST, by site-directed mutagenesis. J Biol Chem, 1995, 270:25207-25212.
18. Vandenberg RJ, Arriza JL, Amara SG, ET al. Constitutive ion fluxes and substrate binding domains of human glutamate transporters. J Biol Chem, 1995, 270:17668-17671.
19. Umbach JA, Coady MJ, Wright EM. Intestinal Na+/glucose cotransporter expressed in Xenopus oocytes is electrogenic. Biolphys J,1990,57:1217-1267.
20. Zhang Y, Pines G, Kanner BL. Histidine 326 is critical for the functiona of GLT-1, a (Na+ +K+)-coupled glutamate transporter from rat brain. J Biol Chem, 1994,269:19573-19577.
21. Kavanaugh MP, Bondahan A, Zerangua N, et al. Mutation of an amino acid residue influencing potassium coupling in the glutamate transporter GLT-1 induces obligate exchange. J Biol Chem, 1997,272:1703-1708.
22. Conradt M, Stoffel W. Functional analysis of the high affinity, Na+-dependent glutamate transporter GLAST-1 by site-directed mutagesis. J Biol Chem, 1995,270:25207-25212.
23. Pines G, Zhang Y, Kanner BI. Glutamate 404 is involved in the substrate disrimination of GLT-1, a (Na++K+) coupled glutamate transporter from rat brain. J Biol Chem, 1995,270:17093-17097.
24. Arriza JL, Fairman WA, Wadiche JI, et al. Functional comparisons of three glutamate transporter substypes cloned from human motor cortex. J Neurosci, 1994,14:5559-5569.
25. Chamberlin AR, Koch HP, Bridge RJ. Design and synthesis of conformationally constrained inhibitors of high-affinity, sodium-dependent glutamate transporters. Methods Enzymol, 1998,296:175-189.
26. Nakayama T, Kawakami H, Tamaka K, et al. Expression of three glutamate transporter subtype mRNAs in human brain regions and peripheral tissues. Mol Brain Res,1996,36:189-192.
27. Velaz-Faircloth M, McGraw TS, Malandro MS, et al. Characterization and distribution of the neuronal glutamate transporter EAAC1 in rat brain. Am J Fhysiol,1996,270:C67-75.
28. Mennerick S, Dhond RP, Benz A, et al. Neuronal expression of the glutamate transporter GLT-1 in hippocampal microculture. J Neurosci, 1998,18:4490-4499.
29. Rothstein JD, Martin L, Leveg AI, et al. Localization of neuronal and glial glutamate transporters. Neuron, 1994,13:713-725.
30. Lehre KP, Levy LM, Ottersen OP, et al. Differential expression of two glial glutamate transporters in the rat brain: J Neurosci, 1995,15:1835-1853.
31. Yamada K, Watanabe M, Shibata T, et al. EAAT4 is a post-synaptic glutamate transporter at Purkinje cell synapses. Neuroreport, 1996,7:2013-2017.
32. Lehre KP, Danbolt NC. The number of glutamate transporter subtype molecules at glutamate synapses: chemical and stereological quantification in young adult rat brain. J Neurosci, 1998,18:8751-8757.
33. Casado M, Zofra F, Aragon C, et al. Activation of high-affinity uptake of glutamate by phorbol esters in primary glial cell cultures. J Neurochem, 1991,57:1185-1190.
34. Conradt M, Stoffel W. Inhibition of the high-affinity brain glutamate transporter GLAST-1 via direct phosphorylation. J Neurochem, 1997,68:1244-1251.
35. Trotti D, Volterra A, Lehre KP, et al. Arachidonic acid inhibits a purified and reconstituted glutamate transporter directly the water phase and not via the phospholipid membrane. J Biol Chem, 1995,270:9890-9895.
36. Barinage M. New accomplices in cell death. Sciencs, 1993,262:1211-1212.
37. Rothstein JD, Dykes-Hoberg M, Pardo CA,et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron, 1996,16:675-686.
38. Fujita H, Sato K, Wen TC, et al. Differential expressions of glycine transporter 1 and three glutamate transporter mRNA in the hippocampus of gerbils with transient forebrain ischemia. J Cereb Blood Flow Metab,1999,19:604-615.
39. Seki Y, Feustel PJ, Keller RW, et al. Inhibition of ischemia-induced glutamate release in rat striatum by dihydrokinate and an anion channel blocker. Stroke, 1999,30:433-440.
40. Inage YW, Itoh M, Wada K,et al. Expression of two glutamate transporters, GLAST and EAAT4, in the human cerebellum: their correlatiom in development and neonatal hypoxic-ischemic damage. J Neuropathol Exp Neurol, 1998,57:554-562.
41. Torp R, Lekieffre D, Levy LM, et al. Reduced postichemic expression of a glial glutamate transporter, GLT1, in the hippocampus. Exp Brain Res, 1995,103:51-58.
42. Gemba T, Oshima T, Ninomiya M. Glutamate efflux via the reversal of the sodium-dependent glutamate transporter caused by glycolytic inhibition in rat cultured astrocytes. Neuroscience, 1994,63:789-795.
43. Peghini P, Janzen J, Stoffel W. Glutamate transporter EAAC1 deffcient mice develop dicarboxylic amino acid uria and behavioral abnormalities but no neurodegeneration. EMBO J,1997,16:3822-3832.
44. Tanaka K, Watase K, Manabe T, et al. Epilepsy and exacerbation of brain injury in mice laking the glutamate transporter GLT-1. Science,1997,276:1699-1702.
45. Akbar MT, Rattary M, Williams RJ, et al. Reduction of GAB A and glutamate transporter messenger RNAs in the severe seizure genetically epilepsy prone rat. Neuroscience,1998,85:1235-1251.
46. Miller HP, Levey AI, Rothstein JD, et al. Alterations in glutamatic transporter protein levels in kindling-induced epilepsy. J Neurochem, 1997,68:1564-1570.
47. Mathern GW, Mendeoza D, Lozada A, et al. Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy. Neurology, 1999,52:453-473.
48. Fray AE, Ince PG, Banner SJ, et al. The expression of the glial glutamate teansporter protein EAAT2 in motor neuron disease: an immunohistochemical study. Eur J Neurosci, 1998,10:2481-2489.
49. Mennini T, Bastone A, Crespi D, et al. Spinal cord GLT-1 glutamate transporter and blood glutamic acid altervations in motor neuron degeneration (Mnd) mice. J Neurol Sci, 1998,157:31-36.
50. Shaw pj, Chinnery RM, Ince PG. [3H] D-aspartate binding sites in the normal human spinal cord and changes in motor neuron disease: a quantitative autoradiographic study. Brain Res,1994,655:195-201.
51. Meldrum BS. The role of glutamate in epilepsy and other CNS disorders. Neurolgy,1994,44(S8):S14-S23.
52. Meldrum BS. Neurotransmission in epilepsy. Epilepsy,1995,36(S1):S30-S35.
53. Greenamyre JT, Porter RHP. Anatomy and physiology of glutamate in the CNS. Neurology,1994,44(S8):S7-S13.
54. Jobe PC, Picchioni AL, Chin L. Role of brain norepinephrine of audiogenic seizure in the rat. J Pharmacol Exp Ther,1973,184:1-10.
55. Mollace V, Bagetta G, Nistico G. Evidence that L-arginine posseses proconvulsant effects mediated through nitric oxide. Neuroreport, 1993,2 ;269-272.
56. De Sarro GB, Di Paola ED, De Sarro A,et al. L-arginine potentiates excitatory amino acid-induced seizures elicited in the deep prepiriform cortex. Eur J Pharmacal,1993,230:151-158.
57. Proctor MR, Fornal F, Afshar JKB,et al. The role of nitric oxide in focally-evoked limbic seizures. Neuroscience, 1997,76:1231-1236.
58. Smith RP, Locus CA, Kruszyna R,et al. Acute neurotoxicity of sodium azide and nitric oxide. Fundam Appl Toxicol, 1991,17:120-127.
59. De Sarro GB, Di Paola ED, De Sarro A,et al. Role of nitric oxide in the genesis of excitatory amino acid-induced seizures from the deep prepiriform cortex. Fundam Clin Pharmacol, 1991,5:503-511.
60. Przewlocka B, Lason W, Machelskaa H,et al. The effects of cocaine-induced seizures on the proenkephalin mRNA level in the mouse hippocampus:a possile involvement of the nitric oxide pathway. Neurosci. Lett,1994:168:81-84.
61. Haaberny KA, Pous S, Eccles CU. Potentiation of quinolinate-induced hippocampal lesions by inhibition of NO synthesiss. Neurosci. Lett, 1992,146:187-190.
62. Manzoni O, Prezeau L, Marin P,et al. Nitric oxide-induced blockade of NMDA receptors. Neuron, 1992,8:653-662.
63. Rondouin G, Bockaert J,Lerner-Natoli M. L-Nitroarginine, an inhibitor of NO synthase, dramatically worsens limbic epilepsy in rats. Neuroport, 1993, 4:1187-1190.
64. Tanaka T, Saito H, Matsuki N. Endogenous nitric oxide inhibits NMDA-and kainate-responses by a negative feedback system in rat hippocampal neurons. Brain ares, 1993, 631:72-76.
65. Grooms SY, Jones LS. Hippocampal in vitro kindling is not blocked by nitric oxide synthase inhibitors. Neuroreport, 1994, 5:1101-1104.
66. Przegalinski E, Baran L, Siwanowicz J. The role of nitric oxide in chemically- and electrically-induced seizures in mice. Neurosci Lett, 1996, 217:145-148.
67. Boda B, Szente M. Nitric oxide synthase inhibitor facilitates focal seizures induced by aminopyridine in rat. Neurosci Lett, 1996, 209: 37-40.
68. Tutka P, Klonowski P, Dzieciuch J, et al. N~G -Nitro-L-arginine differentially affects glutamate- or kainate-induced seizures. Neuroreport, 1996, 7:1605-1608.
69．孙长凯，黄远桂，陈晋文，等．小鼠红藻氨酸诱导性癫痫发作脑组织中NO2-及TBA反应物浓度的变化。中华神经科杂志，1997，30：145-148．
70．陈晋文，黄远桂，孙长凯，等．红藻氨酸诱导性癫痫发作大鼠海马结构与杏仁核中NO2-与cGMP含量的早期变化。中华神经科杂志，1997，30：171．
71．孙长凯，黄远桂．一氧化氮(NO)研究：分子、细胞、免疫与神经科学．中国神经免疫学与神经病学杂志，1995，2：184-186．
72．陈晋文，黄远桂，孙长凯．一氧化氮与癫痫研究．中华神经科杂志．1996，29：252-254．
73．陈晋文，黄远桂，孙长凯．一氧化氮合酶研究的若干进展。生物化学与生物物理进展．1996，23：293-297．
74．孙长凯，黄远桂，莫简等，一氧化氮(NO)生物学与医学研究。心功能杂志，1995，7(3)：16
75. Garthwaite J, Charles SL, Chess-Williams R. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intracellular messenger in the train. Nature, 1988, 336:385-388
76. Bohme GA, Bon C, Stutzmarin JM, et al. Posserble involvement of nitric oxide in long-term potentiation. Eur J Pharmacol, 1991.199:379-381
77. Bon C, Bohme GA, Doble A, et al. A role for nitric oxide in long-term potentiation. Eur J Neurosci, 1992, 4:420-424
78. Haley JE, Wilcox GL, Chapman PE, The role of nitric oxide in hippocampal long-term potentiation, Neuron, 1992, 8:211-216
79. O'Dell TJ, Hawkins RD, Kandel E, et al. Tests of the roles of two diffusible substances in long-term potentiation: evidence for nitrc oxide as a possible early retrograde messenger. Proc Natl Acad Sci USA, 1991, 88:11285-11289
80. Schuman EM, Madison DV. A Requirement for the intercellular messenger nitric oxide in long-term potentiation. Science, 1991, 254: 1503-1506
81. Crepel F, Jaillard D, Protein kinases, nitric oxide and long-term depression of synapses in the cerebellum. NeuroReport, 1990,1:133-136
82. Daniel H, Hemart N, Jaillard D, et al. Long-term depression requires nitric oxide and guanosine 3'. 5' Cyclic monophosphate production in rat cerebellar Purkinje cells. Eur J Neurosci, 1993, 5:1079-1082
83. Ito M, Karachot L, Messengers mediating long-term desensitization in cerebellar Purkinje cells. NeuroReport, 1990, 1:129-134
84. Shibuki K, Okada D, Endogenous nitric oxide release required for long-term synaptic depression in the cerebellum. Nature, 1991,349:172-186
85. Ferraro G, Mantalbano ME, La Grutta V. Nitric oxide and glutamate interaction in the control of cortical and hippocampal excitability. Epilepsia, 1999, 40(7):830-836
86. Chapman PF, Atkins CM, Allen MT, et al. Inhibition of vitric oxide synthesis impairs two different forms of learning. NeuroReport, 1992, 3:567-570
87. Ohkuma S, Narihara H, Katsura,M, et al. Nitric oxide-induced [~3H] GAB A release from cerebral cortical neuren is mediated by peroxynitrite. J Neurochem. 1995, 65:1109-1114
88. Ohkuma S, Katsura M, Chen DZ, et al, Removal of hydroxyl redical increases nitric oxide generators-induced [~3H] GAB A release from mouse cerebral cortical neurens. Neurosci Lett, 1995,194:101-104
89. Ohkuma S, Katsura M, Guo JL, et al. Porticipation of peroxynitrite in acetylcholine release induced by nitric oxide generators. Nearosce Lett, 1995, 183: 151-154
90. Stout AK,Woodward JJ, Differential effects of nitric oxide gas and nitric oxide donors on depolarization-induced release of [~3H] norepinephrine from rat hippocampal slices. Neuropharmacology, 1994,33:1367-1374
91. Lauth D, Hertting G, Jackison R, 3,4-Diaminopyridine-evoked noradrenaline release in rat hippocampal slices; facilitation by endogenous nitric oxide. Brain Res, 1995, 692:174-182
92. Lonart G, Johnson KM, Characterization of nitric oxide geuerator-indvced hippocampal [~3H] nerepinephrine release . The role of glutamate. J Pharmacel Exp Ther, 1995, 275:7-13
93. Ihu XZ, Luo LG. Effect of nitroprusside (nitric oxide) on endogenous depamine release from rat striatal slices. J Neurochem, 1992, 59:932-935
94. Sewart TL, Michel AD, Black MD, et al. Evidence that nitric oxide causes calcium-independent release of [~3H] dopamine from rat striatum in vitro. J Neurochem, 1996, 66:131-137
95. Seilicovich A, Lasaga M, Befumo M, et al.Nitric oxide cunhibits the release of norepinephrine and depamine from the medial basal bypothhalamus of the rat. Proc Natl Aead Sci USA, 1995, 92:11299-11302
96. Kamisaki Y, Wada K, Nakamoto K, et al. Nitric oxide inhibition of the depolarization-evoked glutamate release from synaptosomes of rat cerebellum. Neurosci Lett, 1995,194:5-8
97. Hara S.Kuhus ER, Ellenberger EA, et al. Involvement of nitric oxide in intracerebroventricular β-endorphin-induced neuronal release of methionine-enkepalin. Brain Res. 1995,675:190-194
98. Libri V, Santarelli R, Nistico S, Inhibition of nitric oxide synthase prevents magnesium-free-induced epileptiform activity in guinea-pig piriform covtex neurons in vitro. Naunyn Schmiedebergs Aroh Pharmacol. 1997,355:452-456
99. Itzhak Y, Blokade of sensitization to the toxic effests of cocaine in mice by nitric oxide synthase inhibitors. Pharmacol Toxicol, 1994, 74:162-166
100. Dawson TM, Steiner JP, Dawson VL, et al. Immunosuppressant FK506 enhances phosphorylation of nitric oxide synthase and protects against glutamate neurotoxicity. Proc Natl Acad Sci USA, 193,90:9808-9812
101. Smith SE, Man CM, Yip PK, et al. Auticonvulsant effects of T-nitroindazole in rodents with reflex epilepsy may resul from L-arginine accumulation or a reduction in nitric oxide or L-citrulline formation . Br J Pharmacol, 1996,119:165-173
102. Moggio R, Fumagalli F, Donati E, et al. Inhibition of nitric oxide synthase dramatically potentiates seizures induced by kainic acid and pilocarpine in rats. Brain Res, 1995,679:184-187
103. Herberg LJ, Grottick A, Rose IC, Nitric oxide syuthesis, epileptic seizures and kindlng. Psychopharmacology Berl 1995,119:115-123
104. Snyder SH. Janus faces of nitric oxide .Nature(Lond),1993, 364:577
2. Coyle JT. Neurotoxic action of kainic acid. J.Neuro-chem, 1983,41:1-11.
3. Coyle JT, Puttfarken P. Oxidative stress, glutamate, and neurodegenerative disorder. Science, 1993,262:689-695.
4. Danbolt NC. The high affinity uptake system for excitatory amino acids in the brain. Prog neurobiol, 1994,44:377-396.
5. Kanai Y, Nussberger S, Romoro MF, et al. Electrogenic properties of the epithelial and neuronal high affinity glutamate transporter. J Biol Chem, 1995,270:16561-16568.
6. Bouvier M, Szatkowski M, Amato A, et al. The glial cell glutamate uptake carrier countertransports PH-changing anions. Nature, 1992,360:471-474.
7. Nicholls D, Attwell D. The release and uptake of excitatory amino acids. TIPS, 1990,11:462-468.
8. Stork T, Schulte S, Hoffman K, et al. Structure, expression and functional analysis of a Na+-dependent glutamate/aspartate transporter from rat brain. Proc. Natl. Acad. Sci, 1992,89:10955-10959.
9. Pines G, Danbolt NC, Bjoras M, et al. Cloning and expression of a rat brain L-glutamate transporter. Nature, 1992,360:461-467.
10. Kanai Y, Hediger MA. Primary structure and functional characterization of a high affinity glutamate transporter. Nature, 1992,360:467-471.
11. Ariza JL, Eliasof S, Kavanaugh MP, ET al. Excitatory amino acid transporter 5, aretinal glutamate transporter coupled to a chloride conductance. Proc. Natl. Acad. Sci, 1997, 94:41-55-4160.
12. Maeno-Hikichi Y, Tanaka K, Shibata T, et al. Structure and functional expression of the cloned mouse neuronal high-affinity glutamate transporter. Brain Res Mol Brain Res. 1997, 48:176-180.
13. Eliasof S, Arriza JL, Leighton BH, et al. Excitatory amino acid transporters of the solamander retina: identification, localization, and function. J Neurosci, 1998, 18:698-712.
14. Inoue K, Sakaitani M, Shimada S, et al. Cloning and expression of a bovine glutamate transporter. Brain Res Mol Brain Res, 1995, 28:343-348.
15．高文，饶志仁。神经递质转运体的研究进展。生理科学进展，1997，28：203-208。
16. Levy LK, Chaudhry FA, Honore T, et al. Brain glutamate transporter proteins from homomultimers. J Biol Chem, 1996, 271:27715-27722.
17. Conradt M, Stoffei W. Functional analysis of the high affinity, Na+-dependent glutamate transporter GLAST, by site-directed mutagenesis. J Biol Chem, 1995, 270:25207-25212.
18. Vandenberg RJ, Arriza JL, Amara SG, ET al. Constitutive ion fluxes and substrate binding domains of human glutamate transporters. J Biol Chem, 1995, 270:17668-17671.
19. Umbach JA, Coady MJ, Wright EM. Intestinal Na+/glucose cotransporter expressed in Xenopus oocytes is electrogenic. Biolphys J,1990,57:1217-1267.
20. Zhang Y, Pines G, Kanner BL. Histidine 326 is critical for the functiona of GLT-1, a (Na+ +K+)-coupled glutamate transporter from rat brain. J Biol Chem, 1994,269:19573-19577.
21. Kavanaugh MP, Bondahan A, Zerangua N, et al. Mutation of an amino acid residue influencing potassium coupling in the glutamate transporter GLT-1 induces obligate exchange. J Biol Chem, 1997,272:1703-1708.
22. Conradt M, Stoffel W. Functional analysis of the high affinity, Na+-dependent glutamate transporter GLAST-1 by site-directed mutagesis. J Biol Chem, 1995,270:25207-25212.
23. Pines G, Zhang Y, Kanner BI. Glutamate 404 is involved in the substrate disrimination of GLT-1, a (Na++K+) coupled glutamate transporter from rat brain. J Biol Chem, 1995,270:17093-17097.
24. Arriza JL, Fairman WA, Wadiche JI, et al. Functional comparisons of three glutamate transporter substypes cloned from human motor cortex. J Neurosci, 1994,14:5559-5569.
25. Chamberlin AR, Koch HP, Bridge RJ. Design and synthesis of conformationally constrained inhibitors of high-affinity, sodium-dependent glutamate transporters. Methods Enzymol, 1998,296:175-189.
26. Nakayama T, Kawakami H, Tamaka K, et al. Expression of three glutamate transporter subtype mRNAs in human brain regions and peripheral tissues. Mol Brain Res,1996,36:189-192.
27. Velaz-Faircloth M, McGraw TS, Malandro MS, et al. Characterization and distribution of the neuronal glutamate transporter EAAC1 in rat brain. Am J Fhysiol,1996,270:C67-75.
28. Mennerick S, Dhond RP, Benz A, et al. Neuronal expression of the glutamate transporter GLT-1 in hippocampal microculture. J Neurosci, 1998,18:4490-4499.
29. Rothstein JD, Martin L, Leveg AI, et al. Localization of neuronal and glial glutamate transporters. Neuron, 1994,13:713-725.
30. Lehre KP, Levy LM, Ottersen OP, et al. Differential expression of two glial glutamate transporters in the rat brain: J Neurosci, 1995,15:1835-1853.
31. Yamada K, Watanabe M, Shibata T, et al. EAAT4 is a post-synaptic glutamate transporter at Purkinje cell synapses. Neuroreport, 1996,7:2013-2017.
32. Lehre KP, Danbolt NC. The number of glutamate transporter subtype molecules at glutamate synapses: chemical and stereological quantification in young adult rat brain. J Neurosci, 1998,18:8751-8757.
33. Casado M, Zofra F, Aragon C, et al. Activation of high-affinity uptake of glutamate by phorbol esters in primary glial cell cultures. J Neurochem, 1991,57:1185-1190.
34. Conradt M, Stoffel W. Inhibition of the high-affinity brain glutamate transporter GLAST-1 via direct phosphorylation. J Neurochem, 1997,68:1244-1251.
35. Trotti D, Volterra A, Lehre KP, et al. Arachidonic acid inhibits a purified and reconstituted glutamate transporter directly the water phase and not via the phospholipid membrane. J Biol Chem, 1995,270:9890-9895.
36. Barinage M. New accomplices in cell death. Sciencs, 1993,262:1211-1212.
37. Rothstein JD, Dykes-Hoberg M, Pardo CA,et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron, 1996,16:675-686.
38. Fujita H, Sato K, Wen TC, et al. Differential expressions of glycine transporter 1 and three glutamate transporter mRNA in the hippocampus of gerbils with transient forebrain ischemia. J Cereb Blood Flow Metab,1999,19:604-615.
39. Seki Y, Feustel PJ, Keller RW, et al. Inhibition of ischemia-induced glutamate release in rat striatum by dihydrokinate and an anion channel blocker. Stroke, 1999,30:433-440.
40. Inage YW, Itoh M, Wada K,et al. Expression of two glutamate transporters, GLAST and EAAT4, in the human cerebellum: their correlatiom in development and neonatal hypoxic-ischemic damage. J Neuropathol Exp Neurol, 1998,57:554-562.
41. Torp R, Lekieffre D, Levy LM, et al. Reduced postichemic expression of a glial glutamate transporter, GLT1, in the hippocampus. Exp Brain Res, 1995,103:51-58.
42. Gemba T, Oshima T, Ninomiya M. Glutamate efflux via the reversal of the sodium-dependent glutamate transporter caused by glycolytic inhibition in rat cultured astrocytes. Neuroscience, 1994,63:789-795.
43. Peghini P, Janzen J, Stoffel W. Glutamate transporter EAAC1 deffcient mice develop dicarboxylic amino acid uria and behavioral abnormalities but no neurodegeneration. EMBO J,1997,16:3822-3832.
44. Tanaka K, Watase K, Manabe T, et al. Epilepsy and exacerbation of brain injury in mice laking the glutamate transporter GLT-1. Science,1997,276:1699-1702.
45. Akbar MT, Rattary M, Williams RJ, et al. Reduction of GAB A and glutamate transporter messenger RNAs in the severe seizure genetically epilepsy prone rat. Neuroscience,1998,85:1235-1251.
46. Miller HP, Levey AI, Rothstein JD, et al. Alterations in glutamatic transporter protein levels in kindling-induced epilepsy. J Neurochem, 1997,68:1564-1570.
47. Mathern GW, Mendeoza D, Lozada A, et al. Hippocampal GABA and glutamate transporter immunoreactivity in patients with temporal lobe epilepsy. Neurology, 1999,52:453-473.
48. Fray AE, Ince PG, Banner SJ, et al. The expression of the glial glutamate teansporter protein EAAT2 in motor neuron disease: an immunohistochemical study. Eur J Neurosci, 1998,10:2481-2489.
49. Mennini T, Bastone A, Crespi D, et al. Spinal cord GLT-1 glutamate transporter and blood glutamic acid altervations in motor neuron degeneration (Mnd) mice. J Neurol Sci, 1998,157:31-36.
50. Shaw pj, Chinnery RM, Ince PG. [3H] D-aspartate binding sites in the normal human spinal cord and changes in motor neuron disease: a quantitative autoradiographic study. Brain Res,1994,655:195-201.
51. Meldrum BS. The role of glutamate in epilepsy and other CNS disorders. Neurolgy,1994,44(S8):S14-S23.
52. Meldrum BS. Neurotransmission in epilepsy. Epilepsy,1995,36(S1):S30-S35.
53. Greenamyre JT, Porter RHP. Anatomy and physiology of glutamate in the CNS. Neurology,1994,44(S8):S7-S13.
54. Jobe PC, Picchioni AL, Chin L. Role of brain norepinephrine of audiogenic seizure in the rat. J Pharmacol Exp Ther,1973,184:1-10.
55. Mollace V, Bagetta G, Nistico G. Evidence that L-arginine posseses proconvulsant effects mediated through nitric oxide. Neuroreport, 1993,2 ;269-272.
56. De Sarro GB, Di Paola ED, De Sarro A,et al. L-arginine potentiates excitatory amino acid-induced seizures elicited in the deep prepiriform cortex. Eur J Pharmacal,1993,230:151-158.
57. Proctor MR, Fornal F, Afshar JKB,et al. The role of nitric oxide in focally-evoked limbic seizures. Neuroscience, 1997,76:1231-1236.
58. Smith RP, Locus CA, Kruszyna R,et al. Acute neurotoxicity of sodium azide and nitric oxide. Fundam Appl Toxicol, 1991,17:120-127.
59. De Sarro GB, Di Paola ED, De Sarro A,et al. Role of nitric oxide in the genesis of excitatory amino acid-induced seizures from the deep prepiriform cortex. Fundam Clin Pharmacol, 1991,5:503-511.
60. Przewlocka B, Lason W, Machelskaa H,et al. The effects of cocaine-induced seizures on the proenkephalin mRNA level in the mouse hippocampus:a possile involvement of the nitric oxide pathway. Neurosci. Lett,1994:168:81-84.
61. Haaberny KA, Pous S, Eccles CU. Potentiation of quinolinate-induced hippocampal lesions by inhibition of NO synthesiss. Neurosci. Lett, 1992,146:187-190.
62. Manzoni O, Prezeau L, Marin P,et al. Nitric oxide-induced blockade of NMDA receptors. Neuron, 1992,8:653-662.
63. Rondouin G, Bockaert J,Lerner-Natoli M. L-Nitroarginine, an inhibitor of NO synthase, dramatically worsens limbic epilepsy in rats. Neuroport, 1993, 4:1187-1190.
64. Tanaka T, Saito H, Matsuki N. Endogenous nitric oxide inhibits NMDA-and kainate-responses by a negative feedback system in rat hippocampal neurons. Brain ares, 1993, 631:72-76.
65. Grooms SY, Jones LS. Hippocampal in vitro kindling is not blocked by nitric oxide synthase inhibitors. Neuroreport, 1994, 5:1101-1104.
66. Przegalinski E, Baran L, Siwanowicz J. The role of nitric oxide in chemically- and electrically-induced seizures in mice. Neurosci Lett, 1996, 217:145-148.
67. Boda B, Szente M. Nitric oxide synthase inhibitor facilitates focal seizures induced by aminopyridine in rat. Neurosci Lett, 1996, 209: 37-40.
68. Tutka P, Klonowski P, Dzieciuch J, et al. N~G -Nitro-L-arginine differentially affects glutamate- or kainate-induced seizures. Neuroreport, 1996, 7:1605-1608.
69．孙长凯，黄远桂，陈晋文，等．小鼠红藻氨酸诱导性癫痫发作脑组织中NO2-及TBA反应物浓度的变化。中华神经科杂志，1997，30：145-148．
70．陈晋文，黄远桂，孙长凯，等．红藻氨酸诱导性癫痫发作大鼠海马结构与杏仁核中NO2-与cGMP含量的早期变化。中华神经科杂志，1997，30：171．
71．孙长凯，黄远桂．一氧化氮(NO)研究：分子、细胞、免疫与神经科学．中国神经免疫学与神经病学杂志，1995，2：184-186．
72．陈晋文，黄远桂，孙长凯．一氧化氮与癫痫研究．中华神经科杂志．1996，29：252-254．
73．陈晋文，黄远桂，孙长凯．一氧化氮合酶研究的若干进展。生物化学与生物物理进展．1996，23：293-297．
74．孙长凯，黄远桂，莫简等，一氧化氮(NO)生物学与医学研究。心功能杂志，1995，7(3)：16
75. Garthwaite J, Charles SL, Chess-Williams R. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intracellular messenger in the train. Nature, 1988, 336:385-388
76. Bohme GA, Bon C, Stutzmarin JM, et al. Posserble involvement of nitric oxide in long-term potentiation. Eur J Pharmacol, 1991.199:379-381
77. Bon C, Bohme GA, Doble A, et al. A role for nitric oxide in long-term potentiation. Eur J Neurosci, 1992, 4:420-424
78. Haley JE, Wilcox GL, Chapman PE, The role of nitric oxide in hippocampal long-term potentiation, Neuron, 1992, 8:211-216
79. O'Dell TJ, Hawkins RD, Kandel E, et al. Tests of the roles of two diffusible substances in long-term potentiation: evidence for nitrc oxide as a possible early retrograde messenger. Proc Natl Acad Sci USA, 1991, 88:11285-11289
80. Schuman EM, Madison DV. A Requirement for the intercellular messenger nitric oxide in long-term potentiation. Science, 1991, 254: 1503-1506
81. Crepel F, Jaillard D, Protein kinases, nitric oxide and long-term depression of synapses in the cerebellum. NeuroReport, 1990,1:133-136
82. Daniel H, Hemart N, Jaillard D, et al. Long-term depression requires nitric oxide and guanosine 3'. 5' Cyclic monophosphate production in rat cerebellar Purkinje cells. Eur J Neurosci, 1993, 5:1079-1082
83. Ito M, Karachot L, Messengers mediating long-term desensitization in cerebellar Purkinje cells. NeuroReport, 1990, 1:129-134
84. Shibuki K, Okada D, Endogenous nitric oxide release required for long-term synaptic depression in the cerebellum. Nature, 1991,349:172-186
85. Ferraro G, Mantalbano ME, La Grutta V. Nitric oxide and glutamate interaction in the control of cortical and hippocampal excitability. Epilepsia, 1999, 40(7):830-836
86. Chapman PF, Atkins CM, Allen MT, et al. Inhibition of vitric oxide synthesis impairs two different forms of learning. NeuroReport, 1992, 3:567-570
87. Ohkuma S, Narihara H, Katsura,M, et al. Nitric oxide-induced [~3H] GAB A release from cerebral cortical neuren is mediated by peroxynitrite. J Neurochem. 1995, 65:1109-1114
88. Ohkuma S, Katsura M, Chen DZ, et al, Removal of hydroxyl redical increases nitric oxide generators-induced [~3H] GAB A release from mouse cerebral cortical neurens. Neurosci Lett, 1995,194:101-104
89. Ohkuma S, Katsura M, Guo JL, et al. Porticipation of peroxynitrite in acetylcholine release induced by nitric oxide generators. Nearosce Lett, 1995, 183: 151-154
90. Stout AK,Woodward JJ, Differential effects of nitric oxide gas and nitric oxide donors on depolarization-induced release of [~3H] norepinephrine from rat hippocampal slices. Neuropharmacology, 1994,33:1367-1374
91. Lauth D, Hertting G, Jackison R, 3,4-Diaminopyridine-evoked noradrenaline release in rat hippocampal slices; facilitation by endogenous nitric oxide. Brain Res, 1995, 692:174-182
92. Lonart G, Johnson KM, Characterization of nitric oxide geuerator-indvced hippocampal [~3H] nerepinephrine release . The role of glutamate. J Pharmacel Exp Ther, 1995, 275:7-13
93. Ihu XZ, Luo LG. Effect of nitroprusside (nitric oxide) on endogenous depamine release from rat striatal slices. J Neurochem, 1992, 59:932-935
94. Sewart TL, Michel AD, Black MD, et al. Evidence that nitric oxide causes calcium-independent release of [~3H] dopamine from rat striatum in vitro. J Neurochem, 1996, 66:131-137
95. Seilicovich A, Lasaga M, Befumo M, et al.Nitric oxide cunhibits the release of norepinephrine and depamine from the medial basal bypothhalamus of the rat. Proc Natl Aead Sci USA, 1995, 92:11299-11302
96. Kamisaki Y, Wada K, Nakamoto K, et al. Nitric oxide inhibition of the depolarization-evoked glutamate release from synaptosomes of rat cerebellum. Neurosci Lett, 1995,194:5-8
97. Hara S.Kuhus ER, Ellenberger EA, et al. Involvement of nitric oxide in intracerebroventricular β-endorphin-induced neuronal release of methionine-enkepalin. Brain Res. 1995,675:190-194
98. Libri V, Santarelli R, Nistico S, Inhibition of nitric oxide synthase prevents magnesium-free-induced epileptiform activity in guinea-pig piriform covtex neurons in vitro. Naunyn Schmiedebergs Aroh Pharmacol. 1997,355:452-456
99. Itzhak Y, Blokade of sensitization to the toxic effests of cocaine in mice by nitric oxide synthase inhibitors. Pharmacol Toxicol, 1994, 74:162-166
100. Dawson TM, Steiner JP, Dawson VL, et al. Immunosuppressant FK506 enhances phosphorylation of nitric oxide synthase and protects against glutamate neurotoxicity. Proc Natl Acad Sci USA, 193,90:9808-9812
101. Smith SE, Man CM, Yip PK, et al. Auticonvulsant effects of T-nitroindazole in rodents with reflex epilepsy may resul from L-arginine accumulation or a reduction in nitric oxide or L-citrulline formation . Br J Pharmacol, 1996,119:165-173
102. Moggio R, Fumagalli F, Donati E, et al. Inhibition of nitric oxide synthase dramatically potentiates seizures induced by kainic acid and pilocarpine in rats. Brain Res, 1995,679:184-187
103. Herberg LJ, Grottick A, Rose IC, Nitric oxide syuthesis, epileptic seizures and kindlng. Psychopharmacology Berl 1995,119:115-123
104. Snyder SH. Janus faces of nitric oxide .Nature(Lond),1993, 364:577