内皮素在匹罗卡品致痫大鼠癫痫发作及海马硬化中的作用
摘要
目的
通过观察经侧脑室注射内皮素受体(endothelin receptor, ETR)拮抗剂对匹罗卡品(pilocarpine, Pilo)致痫大鼠急性癫痫发作及海马硬化(hippocampal sclerosis, HS)的影响,进一步了解内源性内皮素(ET)以及ETR亚型在癫痫发生发展中的作用。
方法
氯化锂(lithum chloride, LiCl)联合匹罗卡品小剂量3次重复腹腔注射建立大鼠急性癫痫发作模型。在腹腔注射匹罗卡品前,通过立体定位在大鼠左侧脑室内分别注射容积均为1.5μL的生理盐水(NS)(空白对照组,9只；模型组,30只)、特异性内皮素A受体拮抗剂(ETAR)BQ123(15nmol,30只)特异性ETBR拮抗剂BQ788(15nmol,30只1、ETA&BR非特异性拮抗剂PD145065(15nmol,30只)。建立模型后,观察大鼠的急性期行为学、海马组织匀浆ET含量及海马的病理学改变。
结果
1.空白对照组大鼠未见痫性发作,模型组大鼠有17只(56.7%)出现惊厥性痫性发作(convulsive seizure, CS),其中15只(88.2%)出现癫痫持续状态(status epilepticus, SE)。BQ123及PD145065能显著减少匹罗卡品诱导大鼠CS成功率。BQ788组及PD145065组大鼠匹罗卡品诱导SE发生率显著低于模型组。3个ETR拮抗剂均不影响匹罗卡品诱导大鼠惊厥性痫性发作平均潜伏期。
2.模型组CS大鼠7 d时间点海马组织匀浆ET含量显著高于对照组及3个ETR拮抗剂预处理组。
3.对照组及各组NCS大鼠海马亚区各时间点未出现明显的神经元脱失(neuron loss)。胶质细胞增生(gliosis)与苔藓纤维发芽(mossy fiber sprouting, MFS)。模型组及3个ETR拮抗剂预处理的4组CS大鼠海马CA1、CA3及hilar区在2d、7 d及28 d时间点出现不同程度的神经元脱失与胶质细胞增生。7d时的神经元脱失及胶质细胞增生最严重。CS大鼠CA3区神经元脱失与胶质细胞增生的程度重于CA1,并且海马锥体细胞层胶质细胞增生与神经元脱失相关。28 d时,4组CS大鼠CA3区出现明显的苔藓纤维发芽。海马内ET免疫组化阳性的细胞主要分布在CA区的锥体细胞层,尤以CA3的锥体细胞含量丰富,广泛散在的胶质细胞未见明显的ET表达。
结论
1.内源性ET可能通过作用于中枢性ETAR诱导惊厥性行为的产生,并且很可能通过激活ETBR参与癫痫泛化发展过程,内源性ET至少部分参与了匹罗卡品诱导大鼠急性癫痫发作的发生及发展过程。CS是匹罗卡品诱导海马硬化的重要因素,ETR拮抗剂预处理不能直接阻断匹罗卡品致痫大鼠海马硬化的发生。
2.匹罗卡品致痫大鼠海马组织匀浆中内源性ET在7d时明显升高。海马内ET免疫组化阳性的细胞主要分布在CA区的锥体细胞层,尤以CA3的锥体细胞含量丰富,广泛散在的胶质细胞未见明显的ET表达。
Objective
To better understand the role of endogenous endothelin (ET) and endothelin receptor (ETR) subtypes in the initiation and development of acute epileptic seizures, we observed the effects of intracerebroventricular (ICV) administration of endothelin receptor (ETR) antagonists on piloca-rpine induced acute epileptic seizures and hippocampus sclerosis in rats.
Methods
Repeated low-dose treatment with lithium chloride combined with pilocarpine to produce acute epileptic seizures in rats. Normal saline (control group,9 rats; pilocarpine group, n= 30), a specific endothelin ETAR antagonist (BQ123,15 nmol, n= 30), a specific endothelin ETBR antagonist (BQ788,15 nmol, n= 30) or a non specific endothelin ETA&BR antagonist (PD145065, 15 nmol, n= 30) was ICV administration into the left lateral ventricle of Sprague-Dawley male rats in a total volume of 1.5μL respectively before intraperitoneal (i.p.) injection of pilocarpine. Rats in control group were treated with NS instead of pilocarpine. All pilocarpine induced behavioral alterations, the ET concentration in tissue homogenate of hippocampus and pathological changes were evaluated.
Results
1. No seizures were seen in control group. Pilocarpine produced convulsive seizures (CS) in 56.7% animals of pilocarpine group.88.2% of rats that experienced convulsive seizures developed into SE. BQ123 and significantly decreased the incidence of animals that produced convulsive seizures compared to pilocarpine group. The incidence of rats that showed convulsive seizures subsequently developed SE in BQ788 group and PD145065 group were significant lower than that in pilocarpine group. However, the average latency to onset of convulsive seizure remained no significant differences among all the 4 group of animals treated with pilocarpine.
2. The ET concentration in hippocampal tissue homogenate of rats with convulsive seizu-res in pilocarpine group was significantly higher than control group and the ETR antagonists pretreated animals at 7 d.
3. There is no significant neuron loss, gliosis and mossy fiber sprouting (MFS) in rats of control group and animals with non convulsive seizures (NCS) at each time point. In the CA1、CA3 and hilar subfield, varying degrees of neuron loss and gliosis were observed among 4 groups of animals treated with pilocarpine and developed CS at 7 d and 28 d. The most significant neuron loss and gliosis occur at 7 d time point. It is more severe that the extent of neuron loss and gliosis in CA3 subfield compared to CA1, and gliosis was related to the severity of pyramidal cell loss. The CA3 subfield of all animals developed CS presented significantly MFS at 28 d. The ET immunohistochemistry positive cells mostly located in the pyramidal cell layer, especially the pyramidal cell of CA3 which contained high level of ET. No significant expression of ET was observed in the widespread glial cells.
Conclusions
1. Endogenous ET may produce convulsive seizures by acting on central ETAR, and stimulation of central ETBR may be involved in the generalizing process of epileptic seizures. Endogenous ET, at least, is partly involved in the initiation and development of acute epileptic seizures. CS is an important factory of hippocampal sclerosis, Pretreatment with ETR antagonists can not directly stop the process of hippocampal sclerosis in the rats with lithum-pilocarpine induced CS.
2. Endogenous ET in hippocampal tissue homogenate of rats with lithum-pilocarpine induced CS significantly increases at 7d time point. The ET immunohistochemistry positive cells mostly locate in the pyramidal cell layer of CA subfield, the pyramidal cell of CA3 contains high level of ET. No significant expression of ET is observed in the widespread glial cells.
通过观察经侧脑室注射内皮素受体(endothelin receptor, ETR)拮抗剂对匹罗卡品(pilocarpine, Pilo)致痫大鼠急性癫痫发作及海马硬化(hippocampal sclerosis, HS)的影响,进一步了解内源性内皮素(ET)以及ETR亚型在癫痫发生发展中的作用。
方法
氯化锂(lithum chloride, LiCl)联合匹罗卡品小剂量3次重复腹腔注射建立大鼠急性癫痫发作模型。在腹腔注射匹罗卡品前,通过立体定位在大鼠左侧脑室内分别注射容积均为1.5μL的生理盐水(NS)(空白对照组,9只；模型组,30只)、特异性内皮素A受体拮抗剂(ETAR)BQ123(15nmol,30只)特异性ETBR拮抗剂BQ788(15nmol,30只1、ETA&BR非特异性拮抗剂PD145065(15nmol,30只)。建立模型后,观察大鼠的急性期行为学、海马组织匀浆ET含量及海马的病理学改变。
结果
1.空白对照组大鼠未见痫性发作,模型组大鼠有17只(56.7%)出现惊厥性痫性发作(convulsive seizure, CS),其中15只(88.2%)出现癫痫持续状态(status epilepticus, SE)。BQ123及PD145065能显著减少匹罗卡品诱导大鼠CS成功率。BQ788组及PD145065组大鼠匹罗卡品诱导SE发生率显著低于模型组。3个ETR拮抗剂均不影响匹罗卡品诱导大鼠惊厥性痫性发作平均潜伏期。
2.模型组CS大鼠7 d时间点海马组织匀浆ET含量显著高于对照组及3个ETR拮抗剂预处理组。
3.对照组及各组NCS大鼠海马亚区各时间点未出现明显的神经元脱失(neuron loss)。胶质细胞增生(gliosis)与苔藓纤维发芽(mossy fiber sprouting, MFS)。模型组及3个ETR拮抗剂预处理的4组CS大鼠海马CA1、CA3及hilar区在2d、7 d及28 d时间点出现不同程度的神经元脱失与胶质细胞增生。7d时的神经元脱失及胶质细胞增生最严重。CS大鼠CA3区神经元脱失与胶质细胞增生的程度重于CA1,并且海马锥体细胞层胶质细胞增生与神经元脱失相关。28 d时,4组CS大鼠CA3区出现明显的苔藓纤维发芽。海马内ET免疫组化阳性的细胞主要分布在CA区的锥体细胞层,尤以CA3的锥体细胞含量丰富,广泛散在的胶质细胞未见明显的ET表达。
结论
1.内源性ET可能通过作用于中枢性ETAR诱导惊厥性行为的产生,并且很可能通过激活ETBR参与癫痫泛化发展过程,内源性ET至少部分参与了匹罗卡品诱导大鼠急性癫痫发作的发生及发展过程。CS是匹罗卡品诱导海马硬化的重要因素,ETR拮抗剂预处理不能直接阻断匹罗卡品致痫大鼠海马硬化的发生。
2.匹罗卡品致痫大鼠海马组织匀浆中内源性ET在7d时明显升高。海马内ET免疫组化阳性的细胞主要分布在CA区的锥体细胞层,尤以CA3的锥体细胞含量丰富,广泛散在的胶质细胞未见明显的ET表达。
Objective
To better understand the role of endogenous endothelin (ET) and endothelin receptor (ETR) subtypes in the initiation and development of acute epileptic seizures, we observed the effects of intracerebroventricular (ICV) administration of endothelin receptor (ETR) antagonists on piloca-rpine induced acute epileptic seizures and hippocampus sclerosis in rats.
Methods
Repeated low-dose treatment with lithium chloride combined with pilocarpine to produce acute epileptic seizures in rats. Normal saline (control group,9 rats; pilocarpine group, n= 30), a specific endothelin ETAR antagonist (BQ123,15 nmol, n= 30), a specific endothelin ETBR antagonist (BQ788,15 nmol, n= 30) or a non specific endothelin ETA&BR antagonist (PD145065, 15 nmol, n= 30) was ICV administration into the left lateral ventricle of Sprague-Dawley male rats in a total volume of 1.5μL respectively before intraperitoneal (i.p.) injection of pilocarpine. Rats in control group were treated with NS instead of pilocarpine. All pilocarpine induced behavioral alterations, the ET concentration in tissue homogenate of hippocampus and pathological changes were evaluated.
Results
1. No seizures were seen in control group. Pilocarpine produced convulsive seizures (CS) in 56.7% animals of pilocarpine group.88.2% of rats that experienced convulsive seizures developed into SE. BQ123 and significantly decreased the incidence of animals that produced convulsive seizures compared to pilocarpine group. The incidence of rats that showed convulsive seizures subsequently developed SE in BQ788 group and PD145065 group were significant lower than that in pilocarpine group. However, the average latency to onset of convulsive seizure remained no significant differences among all the 4 group of animals treated with pilocarpine.
2. The ET concentration in hippocampal tissue homogenate of rats with convulsive seizu-res in pilocarpine group was significantly higher than control group and the ETR antagonists pretreated animals at 7 d.
3. There is no significant neuron loss, gliosis and mossy fiber sprouting (MFS) in rats of control group and animals with non convulsive seizures (NCS) at each time point. In the CA1、CA3 and hilar subfield, varying degrees of neuron loss and gliosis were observed among 4 groups of animals treated with pilocarpine and developed CS at 7 d and 28 d. The most significant neuron loss and gliosis occur at 7 d time point. It is more severe that the extent of neuron loss and gliosis in CA3 subfield compared to CA1, and gliosis was related to the severity of pyramidal cell loss. The CA3 subfield of all animals developed CS presented significantly MFS at 28 d. The ET immunohistochemistry positive cells mostly located in the pyramidal cell layer, especially the pyramidal cell of CA3 which contained high level of ET. No significant expression of ET was observed in the widespread glial cells.
Conclusions
1. Endogenous ET may produce convulsive seizures by acting on central ETAR, and stimulation of central ETBR may be involved in the generalizing process of epileptic seizures. Endogenous ET, at least, is partly involved in the initiation and development of acute epileptic seizures. CS is an important factory of hippocampal sclerosis, Pretreatment with ETR antagonists can not directly stop the process of hippocampal sclerosis in the rats with lithum-pilocarpine induced CS.
2. Endogenous ET in hippocampal tissue homogenate of rats with lithum-pilocarpine induced CS significantly increases at 7d time point. The ET immunohistochemistry positive cells mostly locate in the pyramidal cell layer of CA subfield, the pyramidal cell of CA3 contains high level of ET. No significant expression of ET is observed in the widespread glial cells.
引文
[1]王维治,郭玉璞.神经病学[M].北京：人民卫生出版社,2006.993-1059.
[2]吴江.神经病学[M].北京：人民卫生出版社,2005.264-281.
[3]Liu Z, Mikati M, Holmes GL. Mesial temporal sclerosis:pathogenesis and significance [J]. Pediatr Neurol,1995,12(1):5-16.
[4]Zhang X, Cui SS, Wallace AE, et al. Relations between brain pathology and temporal lobe epilepsy [J]. J Neurosci,2002,22(14):6052-6061.
[5]Williamson PD, French JA, Thadani VM, et al. Characteristics of medial temporal lobe epilepsy: Ⅱ. Interictal and ictal scalp electroencephalography, neuropsychological testing, neuroimaging, surgical results, and pathology [J]. Ann Neurol,1993,34(6):781-787.
[6]Babb T, Brown W. Pathological findings in epilepsy. In:Engel J, ed. Surgical treatment in epilepsy [J]. New York:Raven Press,1987:511-540.
[7]Curia G, Longo D, Biagini G, et al. The pilocarpine model of temporal lobe epilepsy [J]. J Neurosci Methods,2008,172(2):143-157.
[8]Amaral DG. A Golgi study of cell types in the hilar region of the hippocampus in the rat [J]. J Comp Neurol,1978,182(4 Pt 2):851-914.
[9]Bayer S. Hippocampal region [A]. In G. Paxinos (Ed.) The Rat Nervous System Voll; Forebrain and Midbrain [C]:New York, Academic Press,1985,335-352.
[10]Amaral DG, Witter MP. The three-dimensional organization of the hippocampal formation:a review of anatomical data [J]. Neuroscience,1989,1(3):571-591.
[11]Witter MP. Connectivity of the rat hippocampus [A]. V. Chan-Palay & C. Kohler (EDs), The Hippocampus-New Vistas, Neurology and Neurobiology Vol X [C]:New York, Alan R. Liss Inc,1989,53-69.
[12]Andersen P. Organization of hippocampal neurons and their interconnections[A]. In R.L. Isaacson & K.H. Pribram (Eds.) The Hippocampus Vol. I[C]:New York, Academic Press,1975.335-352.
[13]Eichenbaum H. A cortical-hippocampal system for declarative memory [J]. Nat Rev Neurosci,2000, 1(1):41-50.
[14]Hjorth-Simonsen A. Projection of the lateral part of the entorhinal area to the hippocampus and fascia dentate [J]. J Comp Neurol,1972,146(2):219-232.
[15]Witter MP. Organization of the entorhinal-hippocampal system: a review of current anatomical data [J]. Hippocampus,1993,3 Spec No:33-44.
[16]Roelink H. Hippocampus formation: an intriguing collaboration [J]. Curr Biol, 2000,10(7):R279-281.
[17]Patton PE, McNaughton B. Connection matrix of the hippocampal formation:Ⅰ. The dentate gyrus [J]. Hippocampus,1995,5(4):245-286.
[18]Frotscher M. Application of the Golgi/electron microscopy technique for cell identification in immunocytochemical, retrograde labeling, and developmental studies of hippocampal neurons [J]. Microsc Res Tech,1992,23(4):306-323.
[19]Christie BR, Cameron HA. Neurogenesis in the adult hippocampus [J]. Hippocampus, 2006,16(3):199-207.
[20]Swanson LW, Wyss JM, Cowan WM. An autoradiographic study of the organization of intrahippocampal association pathways in the rat [J]. J Comp Neurol,1978, 181(4):681-715.
[21]Coulter DA. Chronic epileptogenic cellular alterations in the limbic system after status epilepticus [J]. Epilepsia,1999,40 Suppl 1:S23-33; discussion S40-41.
[22]Frush DP, McNamara JO. Evidence implicating dentate granule cells in wet dog shakes produced by kindling stimulations of entorhinal cortex [J]. Exp Neurol,1986, 92(1):102-113.
[23]Falconer MA, Serafetinides EA, Corsellis JA. Etiology and pathogenesis of temporal lobe epilepsy [J]. Arch Neurol,1964,10:233-248.
[24]Lothman EW, Stringer JL. Functional anatomy of hippocampal seizures [J]. Prog Neurobiol,1991,37(1):1-82.
[25]Bote RP, Blazquez-Llorca L, Fernandez-Gil MA, et al. Hippocampal sclerosis: histopathology substrate and magnetic resonance imaging [J]. Semin Ultrasound CT MR, 2008,29(1):2-14.
[26]Majores M, Schoch S, Lie A, et al. Molecular neuropathology of temporal lobe epilepsy: complementary approaches in animal models and human disease tissue [J]. Epilepsia, 2007,48 Suppl 2:4-12.
[27]Amano S, Ikeda M, Uemura S, et al. Mossy fiber sprouting in the dentate gyrus in a newly developed epileptic mutant, Ihara epileptic rat [J]. Brain Res,1999, 834(1-2):214-218.
[28]Jiao Y, Nadler JV. Stereological analysis of GluR2-immunoreactive hilar neurons in the pilocarpine model of temporal lobe epilepsy:correlation of cell loss with mossy fiber sprouting [J]. Exp Neurol,2007,205(2):569-582.
[29]Cavazos JE, Jones SM, Cross DJ. Sprouting and synaptic reorganization in the subiculum and CA1 region of the hippocampus in acute and chronic models of partial-onset epilepsy [J]. Neuroscience,2004,126(3):677-688.
[30]Fisher PD, Sperber EF, Moshe SL. Hippocampal sclerosis revisited [J]. Brain Dev,1998, 20(8):563-573.
[31]Bower SP, Kilpatrick CJ, Vogrin SJ, et al. Degree of hippocampal atrophy is not related to a history of febrile seizures in patients with proved hippocampal sclerosis [J]. J Neurol Neurosurg Psychiatry,2000,69(6):733-738.
[32]Sommer W. Erkrankung des Ammons Borns alsaetiologisches Moment der Epilepsies [J]. Arch Psychait Nervenkrank,1880,10:631-675.
[33]Van Paesschen W. Qualitative and quantitative imaging of the hippocampus in mesial temporal lobe epilepsy with hippocampal sclerosis [J]. Neuroimaging Clin N Am, 2004,14(3):373-400.
[34]何慧瑾,陈星荣,江澄川.MRI海马结构体积分割分析对颞叶癫痫的诊断价值及临床相关性研究[J].中华放射学杂志,2004,38(12)：53-57.
[35]Hogan RE, Bucholz RD, Joshi S. Hippocampal deformation-based shape analysis in epilepsy and unilateral mesial temporal sclerosis [J]. Epilepsia,2003,44(6):800-806.
[36]Fisher PD, Sperber EF, Moshe SL. Hippocampal sclerosis revisited [J]. Brain Dev,1998, 20(8):563-573.
[37]Sloviter RS. The functional organization of the hippocampal dentate gyrus and its relevance to the pathogenesis of temporal lobe epilepsy [J]. Ann Neurol,1994, 35(6):640-54.
[38]Sloviter RS. Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat:the "dormant basket cell" hypothesis and its possible relevance to temporal lobe epilepsy [J]. Hippocampus,1991, 1(1):41-66.
[39]Sloviter RS. Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy [J]. Science,1987,235(4784):73-76.
[40]McNamara JO. Cellular and molecular basis of epilepsy [J]. J Neurosci, 1994,14(6):3413-425.
[41]Robbins RJ, Brines ML, Kim JH, et al. A selective loss of somatostatin in the hippocampus of patients with temporal lobe epilepsy [J]. Ann Neurol,1991, 29(3):325-332.
[42]Mathern GW, Babb TL, Pretorius JK, et al. Reactive synaptogenesis and neuron densities for neuropeptide Y, somatostatin, and glutamate decarboxylase immunoreactivity in the epileptogenic human fascia dentate [J]. J Neurosci,1995,15(5 Pt 2):3990-4004.
[43]Haas KZ, Sperber EF, Moshe SL, et al. Kainic acid-induced seizures enhance dentate gyrus inhibition by downregulation of GABA(B) receptors [J]. J Neurosci,1996, 16(13):4250-4260.
[44]Buckmaster PS, Dudek FE. Neuron loss, granule cell axon reorganization, and functional changes in the dentate gyrus of epileptic kainate-treated rats [J]. J Comp Neurol,1997, 385(3):385-404.
[45]Nadler JV, Perry BW, Cotman CW. Selective reinnervation of hippocampal area CA1 and the fascia dentata after destruction of CA3-CA4 afferents with kainic acid [J]. Brain Res, 1980,182(1):1-9.
[46]Tauck DL, Nadler JV. Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid-treated rats [J]. J Neurosci,1985,5(4):1016-1022.
[47]Sutula T, He XX, Cavazos J, et al. Synaptic reorganization in the hippocampus induced by abnormal functional activity [J]. Science,1988,239(4844):1147-1150.
[48]Mathern GW, Cifuentes F, Leite JP, et al. Hippocampal EEG excitability and chronic spontaneous seizures are associated with aberrant synaptic reorganization in the rat intrahippocampal kainate model [J]. Electroencephalogr Clin Neurophysiol,1993, 87(5):326-339.
[49]Hickey KA, Rubanyi G, Paul RJ, et al. Characterization of a coronary vasoconstrictor produced by cultured endothelial cells [J]. Am J Physiol,1985,248(5 Pt 1):C550-556.
[50]O'Brien RF, Robbins RJ, McMurtry IF. Endothelial cells in culture produce a vasoconstrictor substance [J]. J Cell Physiol,1987,132(2):263-270.
[51]Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells [J]. Nature,1988,332(6163):411-415.
[52]Maguire JJ, Davenport AP. Is urotensin-II the new endothelin?[J]. Br J Pharmacol, 2002,137(5):579-88.
[53]Luscher TF, Barton M. Endothelins and endothelin receptor antagonists:therapeutic considerations for a novel class of cardiovascular drugs [J]. Circulation,2000, 102(19):2434-2440.
[54]Inoue A, Yanagisawa M, Kimura S, et al. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes [J]. Proc Natl Acad Sci U S A,1989,86(8):2863-2867.
[55]Yanagisawa M, Masaki T. Molecular biology and biochemistry of the endothelins [J]. Trends Pharmacol Sci,1989,10(9):374-378.
[56]Kedzierski RM, Yanagisawa M. Endothelin system: the double-edged sword in health and disease [J]. Annu Rev Pharmacol Toxicol,2001,41:851-876.
[57]Schiffrin EL. Role of endothelin-1 in hypertension and vascular disease [J]. Am J Hypertens,2001,14(6 Pt 2):83S-89S.
[58]Ortmann J, Nett PC, Celeiro J, et al. Endothelin inhibition delays onset of hyperglycemia and associated vascular injury in type I diabetes:evidence for endothelin release by pancreatic islet beta-cells [J]. Biochem Biophys Res Commun,2005,334(2):689-695.
[59]Rubanyi GM, Polokoff MA. Endothelins:molecular biology, biochemistry, pharmacology, physiology, and pathophysiology [J]. Pharmacol Rev,1994,46(3):325-415.
[60]Barton M, Yanagisawa M. Endothelin:20 years from discovery to therapy [J]. Can J Physiol Pharmacol,2008,86(8):485-498.
[61]Sakurai T, Yanagisawa M, Masaki T. Molecular characterization of endothelin receptors [J]. Trends Pharmacol Sci,1992,13(3):103-108.
[62]Hori S, Komatsu Y, Shigemoto R, et al. Distinct tissue distribution and cellular localization of two messenger ribonucleic acids encoding different subtypes of rat endothelin receptors [J]. Endocrinology,1992,130(4):1885-1895.
[63]Masaki T, Vane JR, Vanhoutte PM. International Union of Pharmacology nomenclature of endothelin receptors [J]. Pharmacol Rev,1994,46 (2):137-142.
[64]Webb DJ. Endothelin:from molecule to man [J]. Br J Clin Pharmacol,1997,44(1):9-20.
[65]Zuccarello M, Boccaletti R, Rapoport RM. Does blockade of endothelinB1-receptor activation increase endothelinB2/endothelinA receptor-mediated constriction in the rabbit basilar artery? [J]. J Cardiovasc Pharmacol,1999,33(5):679-684.
[66]Rossi NF, Chen H. Modulation of ET(B) receptor-induced arginine-vasopressin secretion by N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA)-dependent mechanisms in hypothalamo-neurohypophysial explants [J]. Clin Sci (Lond),2002,103 Suppl48:162S-166S.
[67]Calvo JJ, Gonzalez R, De Carvalho LF, et al. Release of substance P from rat hypothalamus and pituitary by endothelin [J]. Endocrinology,1990,126(5):2288-2295.
[68]Kusano E, Akimoto T, Umino T, et al. Modulation of endothelin-1-induced cytosolic free calcium mobilization and mitogen-activated protein kinase activation by erythropoietin in vascular smooth muscle cells [J]. Kidney Blood Press Res,2001,24(3):192-200.
[69]Yoshimi H, Hirata Y, Fukuda Y, et al. Regional distribution of immunoreactive endothelin in rats [J]. Peptides,1989,10(4):805-808.
[70]Greenberg DA, Chan J, Sampson HA. Endothelins and the nervous system [J]. Neurology, 1992,42(1):25-31.
[71]Hemsen A, Lundberg JM. Presence of endothelin-1 and endothelin-3 in peripheral tissues and central nervous system of the pig [J]. Regul Pept,1991,36(1):71-83.
[72]Sluck JM, Lin RC, Katolik LI, et al. Endothelin converting enzyme-1-, endothelin-1-, and endothelin-3-like immunoreactivity in the rat brain [J]. Neuroscience,1999, 91(4):1483-1497.
[73]Pernow J, Hemsen A, Lundberg JM. Tissue specific distribution, clearance and vascular effects of endothelin in the pig [J]. Biochem Biophys Res Commun,1989, 161(2):647-653.
[74]Yoshimoto S, Ishizaki Y, Sasaki T, et al. Effect of carbon dioxide and oxygen on endothelin production by cultured porcine cerebral endothelial cells [J]. Stroke,1991, 22(3):378-383.
[75]Pluta RM, Boock RJ, Afshar JK, et al. Source and cause of endothelin-1 release into cerebrospinal fluid after subarachnoid hemorrhage [J]. J Neurosurg,1997,87(2):287-293.
[76]Lee ME, de la Monte SM, Ng SC, et al. Expression of the potent vasoconstrictor endothelin in the human central nervous system [J]. J Clin Invest,1990,86(1):141-147.
[77]Koseki C, Imai M, Hirata Y, et al. Autoradiographic distribution in rat tissues of binding sites for endothelin:a neuropeptide? [J]. Am J Physiol,1989,256(4 Pt 2):R858-866.
[78]Kuwaki T, Cao WH, Kumada M. Endothelin in the brain and its effect on central control of the circulation and other functions [J]. Jpn J Physiol,1994,44(1):1-18.
[79]Jones CR, Hiley CR, Pelton JT, et al. Autoradiographic localization of endothelin binding sites in kidney [J]. Eur.J.Pharmacol,1989,(163):379-382.
[80]Kurihara M, Ochi A, Kawaguchi T, et al. Localization and characterization of endothelin receptors in human gliomas:a growth factor? [J]. Neurosurgery,1990,27(2):275-281.
[81]Giaid A, Gibson SJ, Herrero MT, et al. Topographical localisation of endothelin mRNA and peptide immunoreactivity in neurones of the human brain [J]. Histochemistry,1991, 95(3):303-314.
[82]Davenport AP, Morton AJ. Binding sites for 1251 ET-1, ET-2, ET-3 and vasoactive intestinal contractor are present in adult rat brain and neurone-enriched primary cultures of embryonic brain cells [J]. Brain Res,1991,54(1-2):278-285.
[83]Yoshimoto S, Ishizaki Y, Kurihara H, et al. Cerebral microvessel endothelium is producing endothelin [J]. Brain Res,1990,508(2):283-285.
[84]Levin ER. Atrial natriuretic peptide and endothelin:interactions in the central nervous system and periphery [J]. Mol Cell Neurosci,1991,2:189-201.
[85]Vigne P, Lopez FA, Frelin C. Na(+)-K(+)-Cl-cotransporter of brain capillary endothelial cells. Properties and regulation by endothelins, hyperosmolar solutions, calyculin A, and interleukin-1 [J]. J Biol Chem,1994,269 (31):19925-19930.
[86]Mortensen LH. Endothelin and the central and peripheral nervous systems:a decade of endothelin research [J]. Clin Exp Pharmacol Physiol,1999,26(12):980-984.
[87]Kuwaki T, Ling GY, Onodera M, et al. Endothelin in the central control of cardiovascular and respiratory functions [J]. Clin Exp Pharmacol Physiol,1999,26(12):989-994.
[88]Ryu JS, Shin CY, Yang SJ, et al. NMDA receptor and NO mediate ET-1-induced behavioral and cardiovascular effects in periaqueductal gray matter of rats [J]. Arch Pharm Res,2001,24 (1):64-8.
[89]Kastner S, Oertel MF, Scharbrodt W, et al. Endothelin-1 in plasma, cisternal CSF and microdialysate following aneurysmal SAH [J]. Acta Neurochir (Wien),2005, 147(12):1271-9; discussion 1279.
[90]Hoffman A, Keiser HR, Grossman E, et al. Endothelin concentrations in cerebrospinal fluid in depressive patients[J]. Lancet,1989,2(8678-8679):1519.
[91]Lampl Y, Fleminger G, Gilad R, et al. Endothelin in cerebrospinal fluid and plasma of patients in the early stage of ischemic stroke [J]. Stroke,1997,28(10):1951-1955.
[92]Goto K, Hama H, Kasuya Y. Molecular pharmacology and pathophysiological significance of endothelin [J]. Jpn J Pharmacol,1996,72(4):261-290.
[93]Gross PM, Weaver DF. A new experimental model of epilepsy based on the intraventricular injection of endothelin [J]. J Cardiovasc Pharmacol,1993,22 Suppl 8:S282-287.
[94]Nagasaka J, Tsuji M, Takeda H, et al. Role of endothelin receptor subtypes in the behavioral effects of the intracerebroventricular administration of endothelin-1 in conscious rats [J]. Pharmacol Biochem Behav,1999,64(1):171-176.
[95]Mateffyova A, Otahal J, Tsenov G, et al. Intrahippocampal injection of endothelin-1 in immature rats results in neuronal death, development of epilepsy and behavioral abnormalities later in life [J]. Eur J Neurosci,2006,24(2):351-60.
[96]梅麒,徐安定,廖卫平,等.海马内注射内皮素一1导致大鼠痫性发作和海马硬化的初步研究[J].中国神经精神疾病杂志,2009,35(05)：276-279.
[97]Shihara M, Hirooka Y, Hori N, et al. Endothelin-1 increases the neuronal activity and augments the responses to glutamate in the NTS [J]. Am J Physiol,1998,275(2 Pt 2):R658-665.
[98]黄怀宇,顾承志,王增辉,等.癫痫发作前后即刻血浆NO、ET_I浓度的研究[J].神经疾病与精神卫生,2002,2(05)：263-264.
[99]Xie JP, Wang XM, Wu XH. The value of serum endothelin for differential diagnosis of the decreased cerebral blood flow perfusion foci of epilepsy patients [J]. Sichuan Da Xue Xue Bao Yi Xue Ban,2004,35(1):80-82.
[100]Kraus GE, Bucholz RD, Yoon KW, et al. Cerebrospinal fluid endothelin-1 and endothelin-3 levels in normal and neurosurgical patients:a clinical study and literature review [J]. Surg.Neurol,1991,35(1):20-29.
[101]邬丽莎,张春来.马桑内酯癫痫大鼠脑内ET mRNA表达的改变[J].泸州医学院学报,2001,24(05)：373-375.
[102]徐安定,吴宜娟,苗海锋,等.内皮素一1诱导培养大鼠大脑皮质神经元凋亡的初步研究[J].中华神经医学杂志,2003,2(01)：45-47.
[103]Salom JB, Torregrosa G, Alborch E. Endothelins and the cerebral circulation [J]. Cerebrovasc Brain Metab Rev,1995,7(2):131-152.
[104]Schmidt-Ott KM, Xu AD, Tuschick S, et al. Hypoxia reverses dibutyryl-cAMP-induced stellation of cultured astrocytes via activation of the endothelin system [J]. FASEB J, 2001,15(7):1227-1229.
[105]Hama H, Kasuya Y, Sakurai T, et al. Role of endothelin-1 in astrocyte responses after acute brain damage [J]. J Neurosci Res,1997,7(6):590-602.
[106]肖争.癫痫模型研究进展[J].1998,27(5)：304-306.
[107]Morimoto K, Fahnestock M, Racine RJ. Kindling and status epilepticus models of epilepsy:rewiring the brain [J]. Prog Neurobiol,2004,73(1):1-60.
[108]Turski WA, Czuczwar SJ, Kleinrok Z, et al. Cholinomimetics produce seizures and brain damage in rats [J]. Experientia,1983,39(12):1408-1411.
[109]Turski WA, Cavalheiro EA, Schwarz M, et al. Limbic seizures produced by pilocarpine in rats:behavioural, electroencephalographic and neuropathological study [J]. Behav Brain Res,1983,9(3):315-335.
[110]Li GL, Xiao B, Xie GJ. Temporal lobe epilepsy model induced by pilocarpine in rats [J]. Hunan Yi Ke Da Xue Xue Bao,2003,28(1):29-32.
[111]Goffin K, Nissinen J, Van Laere K, et al. Cyclicity of spontaneous recurrent seizures in pilocarpine model of temporal lobe epilepsy in rat [J]. Exp Neurol,2007, 205(2):501-505.
[112]Mello LE, Cavalheiro EA, Tan AM, et al. Circuit mechanisms of seizures in the pilocarpine model of chronic epilepsy: cell loss and mossy fiber sprouting [J]. Epilepsia, 1993,34(6):985-995.
[113]Mathern GW, Babb TL, Leite JP, et al. The pathogenic and progressive features of chronic human hippocampal epilepsy [J]. Epilepsy Res,1996,26(1):151-161.
[114]Cavalheiro EA. The pilocarpine model of epilepsy [J]. Ital J Neurol Sci,1995, 16(1-2):33-37.
[115]Turski L, Ikonomidou C, Turski WA, et al. Review: cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine:a novel experimental model of intractable epilepsy [J]. Synapse,1989,3(2):154-171.
[116]Dube C, Marescaux C, Nehlig A. A metabolic and neuropathological approach to the understanding of plastic changes that occur in the immature and adult rat brain during lithium-pilocarpine-induced epileptogenesis [J]. Epilepsia,2000,41 Suppl 6:S36-43.
[117]Dube C, Boyet S, Marescaux C, et al. Relationship between neuronal loss and interictal glucose metabolism during the chronic phase of the lithium-pilocarpine model of epilepsy in the immature and adult rat [J]. Exp Neurol,2001,167(2):227-241.
[118]Leite JP, Bortolotto ZA, Cavalheiro EA. Spontaneous recurrent seizures in rats:an experimental model of partial epilepsy [J]. Neurosci Biobehav Rev,1990,14(4):511-517.
[119]Cavalheiro EA, Leite JP, Bortolotto ZA, et al. Long-term effects of pilocarpine in rats: structural damage of the brain triggers kindling and spontaneous recurrent seizures [J]. Epilepsia,1991,32(6):778-782.
[120]Wieser HG. ILAE Commission Report. Mesial temporal lobe epilepsy with hippocampal sclerosis [J]. Epilepsia,2004,45(6):695-714.
[121]Chakir A, Fabene PF, Ouazzani R, et al. Drug resistance and hippocampal damage after delayed treatment of pilocarpine-induced epilepsy in the rat [J]. Brain Res Bull,2006, 71(1-3):127-138.
[122]Glien M, Brandt C, Potschka H, et al. Effects of the novel antiepileptic drug levetiracetam on spontaneous recurrent seizures in the rat pilocarpine model of temporal lobe epilepsy[J]. Epilepsia,2002,43(4):350-357.
[123]George Paxinos CW. The rat brain in stereotaxic coordinates (3rd edition) [M], Academic Press,1996.
[124]Racine RJ. Modification of seizure activity by electrical stimulation. Ⅱ. Motor seizure [J]. Electroencephalogr Clin Neurophysiol,1972,32(3):281-294.
[125]Glien M, Brandt C, Potschka H, et al. Repeated low-dose treatment of rats with pilocarpine:low mortality but high proportion of rats developing epilepsy [J]. Epilepsy Res,2001,46(2):111-119.
[126]Borges K, Gearing M, McDermott DL, et al. Neuronal and glial pathological changes during epileptogenesis in the mouse pilocarpine model [J]. Exp Neurol,2003, 182(1):21-34.
[127]Brunello AG, Weissenberger J, Kappeler A, et al. Astrocytic alterations in interleukin-6/Soluble interleukin-6 receptor alpha double-transgenic mice [J]. Am J Pathol,2000,157(5):1485-1493.
[128]Holmes GL, Sarkisian M, Ben-Ari Y, et al. Mossy fiber sprouting after recurrent seizures during early development in rats [J]. J Comp Neurol,1999,404(4):537-553.
[129]Holmes GL, Gairsa JL, Chevassus-Au-Louis N, et al. Consequences of neonatal seizures in the rat: morphological and behavioral effects [J]. Ann Neurol,1998,44(6):845-857.
[130]Hamilton SE, Loose MD, Qi M, et al. Disruption of the ml receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice [J]. Proc Natl Acad Sci U S A,1997,94(24):13311-13116.
[131]Smolders I, Khan GM, Manil J, et al. NMDA receptor-mediated pilocarpine-induced seizures:characterization in freely moving rats by microdialysis [J]. Br J Pharmacol, 1997,121(6):1171-1179.
[132]Meurs A, Clinckers R, Ebinger G, et al. Seizure activity and changes in hippocampal extracellular glutamate, GABA, dopamine and serotonin [J]. Epilepsy Res,2008, 78(1):50-59.
[133]Markram H, Segal M. Long-lasting facilitation of excitatory postsynaptic potentials in the rat hippocampus by acetylcholine [J]. J Physiol,1990,427:381-393.
[134]Smolders I, Bogaert L, Ebinger G, et al. Muscarinic modulation of striatal dopamine, glutamate, and GAB A release, as measured with in vivo microdialysis [J]. J Neurochem,' 1997,68(5):1942-1948.
[135]den Buuse M v, Webber KM. Endothelin and dopamine release [J]. Prog Neurobiol,2000, 60(4):385-405.
[136]Clinckers R, Smolders I, Meurs A, et al. Anticonvulsant action of hippocampal dopamine and serotonin is independently mediated by D and 5-HT receptors [J]. J Neurochem, 2004,89(4):834-843.
[137]谢建平,吴晓华.血浆内皮素水平对癫痫的诊断和鉴别诊断价值[J].四川大学学报(医学版),2004,35(01)：80-82.
[138]袁定新.海马硬化与癫痫[J].医学理论与实践,2007,20(05)：525-527.
[139]Morita H, Suzuki K, Mori N, et al. Occurrence of complement protein C3 in dying pyramidal neurons in rat hippocampus after systemic administration of kainic acid [J]. Neurosci Lett,2006,409(1):35-40.
[140]Monoghan DTC, C.W. Distribution of N-methyl-d-aspartatesensitive L-[3H] glutamate-binding sites in rat brain [J]. J Neurosci,1985,5:2909-2919.
[141]Sloviter RS, Sollas AL, Barbaro NM, et al. Calcium-binding protein (calbindin-D28K) and parvalbumin immunocytochemistry in the normal and epileptic human hippocampus [J]. J Comp Neurol,1991,308(3):381-96.
[142]孙殿荣.癫痫发病机制的研究进展[J].华西医学,2004,19(03)：524-525.
[143]Wasterlain CG, Shirasaka Y, Mazarati AM, et al. Chronic epilepsy with damage restricted to the hippocampus:possible mechanisms [J]. Epilepsy Res,1996,26(1):255-265.
[144]Johansen FF. Interneurons in rat hippocampus after cerebral ischemia. Morphometric, functional, and therapeutic investigations [J]. Acta Neurol Scand Suppl,1993,150:1-32.
[145]陈刚,邓艳春,王小木,等.癫痫大鼠海马神经元和星形胶质细胞的病理演变[J].中华神经外科疾病研究杂志,2007,6(03)：229-232.
[146]Tsenov G, Mateffyova A, Mares P, et al. Intrahippocampal injection of endothelin-1:a new model of ischemia-induced seizures in immature rats [J]. Epilepsia,2007,48 Suppl 5:7-13.
[147]Peredery O, Persinger MA, Parker G, et al. Temporal changes in neuronal dropout following inductions of lithium/pilocarpine seizures in the rat [J]. Brain Res,2000, 881(1):9-17.
[148]Magloczky Z, Freund TF. Delayed cell death in the contralateral hippocampus following kainate injection into the CA3 subfield [J]. Neuroscience,1995,66(4):847-860.
[149]Wang L, Liu YH, Huang YG, et al. Time-course of neuronal death in the mouse pilocarpine model of chronic epilepsy using Fluoro-Jade C staining [J]. Brain Res,2008, 1241:157-167.
[150]Houser CR, Miyashiro JE, Swartz BE, et al. Altered patterns of dynorphin immunoreactivity suggest mossy fiber reorganization in human hippocampal epilepsy [J]. J Neurosci,1990,10(1):267-282.
[151]Babb TL, Kupfer WR, Pretorius JK, et al. Synaptic reorganization by mossy fibers in human epileptic fascia dentate [J]. Neuroscience,1991,42(2):351-363.
[152]周铨,朱丹.颞叶癫痫患者海马硬化神经元脱失的亚群特点[J].中华神经医学杂志,2005,4(07)：677-679.
[153]Buckmaster PS, Jongen-Relo AL. Highly specific neuron loss preserves lateral inhibitory circuits in the dentate gyrus of kainate-induced epileptic rats [J]. J Neurosci,1999, 19(21):9519-9529.
[154]Briellmann RS, Kalnins RM, Berkovic SF, et al. Hippocampal pathology in refractory temporal lobe epilepsy:T2-weighted signal change reflects dentate gliosis [J]. Neurology, 2002,58(2):265-271.
[155]Vessal M, Dugani CB, Solomon DA, et al. Might astrocytes play a role in maintaining the seizure-prone state? [J]. Brain Res,2005,1044(2):190-196.
[156]Binder DK, Steinhauser C. Functional changes in astroglial cells in epilepsy [J]. Glia, 2006,54(5):358-368.
[157]Kang TC, Kim DS, Kwak SE, et al. Epileptogenic roles of astroglial death and regeneration in the dentate gyrus of experimental temporal lobe epilepsy [J]. Glia,2006, 54(4):258-271.
[158]Garzillo CL, Mello LE. Characterization of reactive astrocytes in the chronic phase of the pilocarpine model of epilepsy [J]. Epilepsia,2002,43 Suppl 5:107-109.
[159]Lee SH, Magge S, Spencer DD, et al. Human epileptic astrocytes exhibit increased gap junction coupling [J]. Glia,1995,15(2):195-202.
[160]Griffin WS, Yeralan O, Sheng JG, et al. Overexpression of the neurotrophic cytokine S100 beta in human temporal lobe epilepsy [J]. J Neurochem,1995,65(1):228-233.
[161]Penkowa M, Molinero A, Carrasco J, et al. Interleukin-6 deficiency reduces the brain inflammatory response and increases oxidative stress and neurodegeneration after kainic acid-induced seizures [J]. Neuroscience,2001,102(4):805-818.
[162]张秀丽.星型细胞在癫痫发病机制中作用的研究进展[J].国外医学.神经病学神经外科学分册,2001,28(01)：38-40.
[163]Nadler JV. The recurrent mossy fiber pathway of the epileptic brain [J]. Neurochem Res, 2003,28(11):1649-1658.
[164]Feng L, Molnar P, Nadler JV. Short-term frequency-dependent plasticity at recurrent mossy fiber synapses of the epileptic brain [J]. J Neurosci,2003,23(12):5381-5390.
[165]Wuarin JP, Dudek FE. Electrographic seizures and new recurrent excitatory circuits in the dentate gyrus of hippocampal slices from kainate-treated epileptic rats [J]. J Neurosci, 1996,16(14):4438-4448.
[166]Steward O. Reinnervation of dentate gyrus by homologous afferents following entorhinal cortical lesions in adult rats [J]. Science,1976,194(4263):426-428.
[167]Vezzani A, Civenni G, Rizzi M, et al. Enhanced neuropeptide Y release in the hippocampus is associated with chronic seizure susceptibility in kainic acid treated rats [J]. Brain Res,1994,660(1):138-143.
[168]Proper EA, Jansen GH, van VCW, et al. A grading system for hippocampal sclerosis based on the degree of hippocampal mossy fiber sprouting [J]. Acta Neuropathol,2001, 101(4):405-409.
[169]Okazaki MM, Evenson DA, Nadler JV. Hippocampal mossy fiber sprouting and synapse formation after status epilepticus in rats:visualization after retrograde transport of biocytin [J]. J Comp Neurol,1995,352(4):515-534.
[170]Cavazos JE, Zhang P, Qazi R, et al. Ultrastructural features of sprouted mossy fiber synapses in kindled and kainic acid-treated rats [J]. J Comp Neurol,2003, 458(3):272-292.
[171]Buckmaster PS, Zhang GF, Yamawaki R. Axon sprouting in a model of temporal lobe epilepsy creates a predominantly excitatory feedback circuit [J]. J Neurosci,2002, 22(15):6650-6658.
[172]Nadler JV, Okazaki MM, Gruenthal M, et al. Kainic acid seizures and neuronal cell death: insights from studies of selective lesions and drugs [J]. Adv Exp Med Biol,1986, 203:673-686.
[173]Post RM, Weiss SR. Convergences in course of illness and treatments of the epilepsies and recurrent affective disorders [J]. Clin EEG Neurosci,2004,35(1):14-24.
[174]李国良.海马苔藓纤维出芽与颞叶癫痫[J].国外医学(神经病学神经外科学分册),2002,29(06)：515-518.
[175]Lemos T, Cavalheiro EA. Suppression of pilocarpine-induced status epilepticus and the late development of epilepsy in rats [J]. Exp Brain Res,1995,102(3):423-428.
[176]Jessberger S, Romer B, Babu H, et al. Seizures induce proliferation and dispersion of doublecortin-positive hippocampal progenitor cells [J]. Exp Neurol,2005, 196(2):342-351.
[177]Anderson CM, Swanson RA. Astrocyte glutamate transport:review of properties, regulation, and physiological functions [J]. Glia,2000,32(1):1-14.
[178]Hinterkeuser S, Schroder W, Hager G, et al. Astrocytes in the hippocampus of patients with temporal lobe epilepsy display changes in potassium conductances [J]. Eur J Neurosci,2000,12(6):2087-2096.
[179]Barres BA, Barde Y. Neuronal and glial cell biology [J]. Curr Opin Neurobiol,2000, 10(5):642-648.
[2]吴江.神经病学[M].北京：人民卫生出版社,2005.264-281.
[3]Liu Z, Mikati M, Holmes GL. Mesial temporal sclerosis:pathogenesis and significance [J]. Pediatr Neurol,1995,12(1):5-16.
[4]Zhang X, Cui SS, Wallace AE, et al. Relations between brain pathology and temporal lobe epilepsy [J]. J Neurosci,2002,22(14):6052-6061.
[5]Williamson PD, French JA, Thadani VM, et al. Characteristics of medial temporal lobe epilepsy: Ⅱ. Interictal and ictal scalp electroencephalography, neuropsychological testing, neuroimaging, surgical results, and pathology [J]. Ann Neurol,1993,34(6):781-787.
[6]Babb T, Brown W. Pathological findings in epilepsy. In:Engel J, ed. Surgical treatment in epilepsy [J]. New York:Raven Press,1987:511-540.
[7]Curia G, Longo D, Biagini G, et al. The pilocarpine model of temporal lobe epilepsy [J]. J Neurosci Methods,2008,172(2):143-157.
[8]Amaral DG. A Golgi study of cell types in the hilar region of the hippocampus in the rat [J]. J Comp Neurol,1978,182(4 Pt 2):851-914.
[9]Bayer S. Hippocampal region [A]. In G. Paxinos (Ed.) The Rat Nervous System Voll; Forebrain and Midbrain [C]:New York, Academic Press,1985,335-352.
[10]Amaral DG, Witter MP. The three-dimensional organization of the hippocampal formation:a review of anatomical data [J]. Neuroscience,1989,1(3):571-591.
[11]Witter MP. Connectivity of the rat hippocampus [A]. V. Chan-Palay & C. Kohler (EDs), The Hippocampus-New Vistas, Neurology and Neurobiology Vol X [C]:New York, Alan R. Liss Inc,1989,53-69.
[12]Andersen P. Organization of hippocampal neurons and their interconnections[A]. In R.L. Isaacson & K.H. Pribram (Eds.) The Hippocampus Vol. I[C]:New York, Academic Press,1975.335-352.
[13]Eichenbaum H. A cortical-hippocampal system for declarative memory [J]. Nat Rev Neurosci,2000, 1(1):41-50.
[14]Hjorth-Simonsen A. Projection of the lateral part of the entorhinal area to the hippocampus and fascia dentate [J]. J Comp Neurol,1972,146(2):219-232.
[15]Witter MP. Organization of the entorhinal-hippocampal system: a review of current anatomical data [J]. Hippocampus,1993,3 Spec No:33-44.
[16]Roelink H. Hippocampus formation: an intriguing collaboration [J]. Curr Biol, 2000,10(7):R279-281.
[17]Patton PE, McNaughton B. Connection matrix of the hippocampal formation:Ⅰ. The dentate gyrus [J]. Hippocampus,1995,5(4):245-286.
[18]Frotscher M. Application of the Golgi/electron microscopy technique for cell identification in immunocytochemical, retrograde labeling, and developmental studies of hippocampal neurons [J]. Microsc Res Tech,1992,23(4):306-323.
[19]Christie BR, Cameron HA. Neurogenesis in the adult hippocampus [J]. Hippocampus, 2006,16(3):199-207.
[20]Swanson LW, Wyss JM, Cowan WM. An autoradiographic study of the organization of intrahippocampal association pathways in the rat [J]. J Comp Neurol,1978, 181(4):681-715.
[21]Coulter DA. Chronic epileptogenic cellular alterations in the limbic system after status epilepticus [J]. Epilepsia,1999,40 Suppl 1:S23-33; discussion S40-41.
[22]Frush DP, McNamara JO. Evidence implicating dentate granule cells in wet dog shakes produced by kindling stimulations of entorhinal cortex [J]. Exp Neurol,1986, 92(1):102-113.
[23]Falconer MA, Serafetinides EA, Corsellis JA. Etiology and pathogenesis of temporal lobe epilepsy [J]. Arch Neurol,1964,10:233-248.
[24]Lothman EW, Stringer JL. Functional anatomy of hippocampal seizures [J]. Prog Neurobiol,1991,37(1):1-82.
[25]Bote RP, Blazquez-Llorca L, Fernandez-Gil MA, et al. Hippocampal sclerosis: histopathology substrate and magnetic resonance imaging [J]. Semin Ultrasound CT MR, 2008,29(1):2-14.
[26]Majores M, Schoch S, Lie A, et al. Molecular neuropathology of temporal lobe epilepsy: complementary approaches in animal models and human disease tissue [J]. Epilepsia, 2007,48 Suppl 2:4-12.
[27]Amano S, Ikeda M, Uemura S, et al. Mossy fiber sprouting in the dentate gyrus in a newly developed epileptic mutant, Ihara epileptic rat [J]. Brain Res,1999, 834(1-2):214-218.
[28]Jiao Y, Nadler JV. Stereological analysis of GluR2-immunoreactive hilar neurons in the pilocarpine model of temporal lobe epilepsy:correlation of cell loss with mossy fiber sprouting [J]. Exp Neurol,2007,205(2):569-582.
[29]Cavazos JE, Jones SM, Cross DJ. Sprouting and synaptic reorganization in the subiculum and CA1 region of the hippocampus in acute and chronic models of partial-onset epilepsy [J]. Neuroscience,2004,126(3):677-688.
[30]Fisher PD, Sperber EF, Moshe SL. Hippocampal sclerosis revisited [J]. Brain Dev,1998, 20(8):563-573.
[31]Bower SP, Kilpatrick CJ, Vogrin SJ, et al. Degree of hippocampal atrophy is not related to a history of febrile seizures in patients with proved hippocampal sclerosis [J]. J Neurol Neurosurg Psychiatry,2000,69(6):733-738.
[32]Sommer W. Erkrankung des Ammons Borns alsaetiologisches Moment der Epilepsies [J]. Arch Psychait Nervenkrank,1880,10:631-675.
[33]Van Paesschen W. Qualitative and quantitative imaging of the hippocampus in mesial temporal lobe epilepsy with hippocampal sclerosis [J]. Neuroimaging Clin N Am, 2004,14(3):373-400.
[34]何慧瑾,陈星荣,江澄川.MRI海马结构体积分割分析对颞叶癫痫的诊断价值及临床相关性研究[J].中华放射学杂志,2004,38(12)：53-57.
[35]Hogan RE, Bucholz RD, Joshi S. Hippocampal deformation-based shape analysis in epilepsy and unilateral mesial temporal sclerosis [J]. Epilepsia,2003,44(6):800-806.
[36]Fisher PD, Sperber EF, Moshe SL. Hippocampal sclerosis revisited [J]. Brain Dev,1998, 20(8):563-573.
[37]Sloviter RS. The functional organization of the hippocampal dentate gyrus and its relevance to the pathogenesis of temporal lobe epilepsy [J]. Ann Neurol,1994, 35(6):640-54.
[38]Sloviter RS. Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat:the "dormant basket cell" hypothesis and its possible relevance to temporal lobe epilepsy [J]. Hippocampus,1991, 1(1):41-66.
[39]Sloviter RS. Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy [J]. Science,1987,235(4784):73-76.
[40]McNamara JO. Cellular and molecular basis of epilepsy [J]. J Neurosci, 1994,14(6):3413-425.
[41]Robbins RJ, Brines ML, Kim JH, et al. A selective loss of somatostatin in the hippocampus of patients with temporal lobe epilepsy [J]. Ann Neurol,1991, 29(3):325-332.
[42]Mathern GW, Babb TL, Pretorius JK, et al. Reactive synaptogenesis and neuron densities for neuropeptide Y, somatostatin, and glutamate decarboxylase immunoreactivity in the epileptogenic human fascia dentate [J]. J Neurosci,1995,15(5 Pt 2):3990-4004.
[43]Haas KZ, Sperber EF, Moshe SL, et al. Kainic acid-induced seizures enhance dentate gyrus inhibition by downregulation of GABA(B) receptors [J]. J Neurosci,1996, 16(13):4250-4260.
[44]Buckmaster PS, Dudek FE. Neuron loss, granule cell axon reorganization, and functional changes in the dentate gyrus of epileptic kainate-treated rats [J]. J Comp Neurol,1997, 385(3):385-404.
[45]Nadler JV, Perry BW, Cotman CW. Selective reinnervation of hippocampal area CA1 and the fascia dentata after destruction of CA3-CA4 afferents with kainic acid [J]. Brain Res, 1980,182(1):1-9.
[46]Tauck DL, Nadler JV. Evidence of functional mossy fiber sprouting in hippocampal formation of kainic acid-treated rats [J]. J Neurosci,1985,5(4):1016-1022.
[47]Sutula T, He XX, Cavazos J, et al. Synaptic reorganization in the hippocampus induced by abnormal functional activity [J]. Science,1988,239(4844):1147-1150.
[48]Mathern GW, Cifuentes F, Leite JP, et al. Hippocampal EEG excitability and chronic spontaneous seizures are associated with aberrant synaptic reorganization in the rat intrahippocampal kainate model [J]. Electroencephalogr Clin Neurophysiol,1993, 87(5):326-339.
[49]Hickey KA, Rubanyi G, Paul RJ, et al. Characterization of a coronary vasoconstrictor produced by cultured endothelial cells [J]. Am J Physiol,1985,248(5 Pt 1):C550-556.
[50]O'Brien RF, Robbins RJ, McMurtry IF. Endothelial cells in culture produce a vasoconstrictor substance [J]. J Cell Physiol,1987,132(2):263-270.
[51]Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells [J]. Nature,1988,332(6163):411-415.
[52]Maguire JJ, Davenport AP. Is urotensin-II the new endothelin?[J]. Br J Pharmacol, 2002,137(5):579-88.
[53]Luscher TF, Barton M. Endothelins and endothelin receptor antagonists:therapeutic considerations for a novel class of cardiovascular drugs [J]. Circulation,2000, 102(19):2434-2440.
[54]Inoue A, Yanagisawa M, Kimura S, et al. The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes [J]. Proc Natl Acad Sci U S A,1989,86(8):2863-2867.
[55]Yanagisawa M, Masaki T. Molecular biology and biochemistry of the endothelins [J]. Trends Pharmacol Sci,1989,10(9):374-378.
[56]Kedzierski RM, Yanagisawa M. Endothelin system: the double-edged sword in health and disease [J]. Annu Rev Pharmacol Toxicol,2001,41:851-876.
[57]Schiffrin EL. Role of endothelin-1 in hypertension and vascular disease [J]. Am J Hypertens,2001,14(6 Pt 2):83S-89S.
[58]Ortmann J, Nett PC, Celeiro J, et al. Endothelin inhibition delays onset of hyperglycemia and associated vascular injury in type I diabetes:evidence for endothelin release by pancreatic islet beta-cells [J]. Biochem Biophys Res Commun,2005,334(2):689-695.
[59]Rubanyi GM, Polokoff MA. Endothelins:molecular biology, biochemistry, pharmacology, physiology, and pathophysiology [J]. Pharmacol Rev,1994,46(3):325-415.
[60]Barton M, Yanagisawa M. Endothelin:20 years from discovery to therapy [J]. Can J Physiol Pharmacol,2008,86(8):485-498.
[61]Sakurai T, Yanagisawa M, Masaki T. Molecular characterization of endothelin receptors [J]. Trends Pharmacol Sci,1992,13(3):103-108.
[62]Hori S, Komatsu Y, Shigemoto R, et al. Distinct tissue distribution and cellular localization of two messenger ribonucleic acids encoding different subtypes of rat endothelin receptors [J]. Endocrinology,1992,130(4):1885-1895.
[63]Masaki T, Vane JR, Vanhoutte PM. International Union of Pharmacology nomenclature of endothelin receptors [J]. Pharmacol Rev,1994,46 (2):137-142.
[64]Webb DJ. Endothelin:from molecule to man [J]. Br J Clin Pharmacol,1997,44(1):9-20.
[65]Zuccarello M, Boccaletti R, Rapoport RM. Does blockade of endothelinB1-receptor activation increase endothelinB2/endothelinA receptor-mediated constriction in the rabbit basilar artery? [J]. J Cardiovasc Pharmacol,1999,33(5):679-684.
[66]Rossi NF, Chen H. Modulation of ET(B) receptor-induced arginine-vasopressin secretion by N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA)-dependent mechanisms in hypothalamo-neurohypophysial explants [J]. Clin Sci (Lond),2002,103 Suppl48:162S-166S.
[67]Calvo JJ, Gonzalez R, De Carvalho LF, et al. Release of substance P from rat hypothalamus and pituitary by endothelin [J]. Endocrinology,1990,126(5):2288-2295.
[68]Kusano E, Akimoto T, Umino T, et al. Modulation of endothelin-1-induced cytosolic free calcium mobilization and mitogen-activated protein kinase activation by erythropoietin in vascular smooth muscle cells [J]. Kidney Blood Press Res,2001,24(3):192-200.
[69]Yoshimi H, Hirata Y, Fukuda Y, et al. Regional distribution of immunoreactive endothelin in rats [J]. Peptides,1989,10(4):805-808.
[70]Greenberg DA, Chan J, Sampson HA. Endothelins and the nervous system [J]. Neurology, 1992,42(1):25-31.
[71]Hemsen A, Lundberg JM. Presence of endothelin-1 and endothelin-3 in peripheral tissues and central nervous system of the pig [J]. Regul Pept,1991,36(1):71-83.
[72]Sluck JM, Lin RC, Katolik LI, et al. Endothelin converting enzyme-1-, endothelin-1-, and endothelin-3-like immunoreactivity in the rat brain [J]. Neuroscience,1999, 91(4):1483-1497.
[73]Pernow J, Hemsen A, Lundberg JM. Tissue specific distribution, clearance and vascular effects of endothelin in the pig [J]. Biochem Biophys Res Commun,1989, 161(2):647-653.
[74]Yoshimoto S, Ishizaki Y, Sasaki T, et al. Effect of carbon dioxide and oxygen on endothelin production by cultured porcine cerebral endothelial cells [J]. Stroke,1991, 22(3):378-383.
[75]Pluta RM, Boock RJ, Afshar JK, et al. Source and cause of endothelin-1 release into cerebrospinal fluid after subarachnoid hemorrhage [J]. J Neurosurg,1997,87(2):287-293.
[76]Lee ME, de la Monte SM, Ng SC, et al. Expression of the potent vasoconstrictor endothelin in the human central nervous system [J]. J Clin Invest,1990,86(1):141-147.
[77]Koseki C, Imai M, Hirata Y, et al. Autoradiographic distribution in rat tissues of binding sites for endothelin:a neuropeptide? [J]. Am J Physiol,1989,256(4 Pt 2):R858-866.
[78]Kuwaki T, Cao WH, Kumada M. Endothelin in the brain and its effect on central control of the circulation and other functions [J]. Jpn J Physiol,1994,44(1):1-18.
[79]Jones CR, Hiley CR, Pelton JT, et al. Autoradiographic localization of endothelin binding sites in kidney [J]. Eur.J.Pharmacol,1989,(163):379-382.
[80]Kurihara M, Ochi A, Kawaguchi T, et al. Localization and characterization of endothelin receptors in human gliomas:a growth factor? [J]. Neurosurgery,1990,27(2):275-281.
[81]Giaid A, Gibson SJ, Herrero MT, et al. Topographical localisation of endothelin mRNA and peptide immunoreactivity in neurones of the human brain [J]. Histochemistry,1991, 95(3):303-314.
[82]Davenport AP, Morton AJ. Binding sites for 1251 ET-1, ET-2, ET-3 and vasoactive intestinal contractor are present in adult rat brain and neurone-enriched primary cultures of embryonic brain cells [J]. Brain Res,1991,54(1-2):278-285.
[83]Yoshimoto S, Ishizaki Y, Kurihara H, et al. Cerebral microvessel endothelium is producing endothelin [J]. Brain Res,1990,508(2):283-285.
[84]Levin ER. Atrial natriuretic peptide and endothelin:interactions in the central nervous system and periphery [J]. Mol Cell Neurosci,1991,2:189-201.
[85]Vigne P, Lopez FA, Frelin C. Na(+)-K(+)-Cl-cotransporter of brain capillary endothelial cells. Properties and regulation by endothelins, hyperosmolar solutions, calyculin A, and interleukin-1 [J]. J Biol Chem,1994,269 (31):19925-19930.
[86]Mortensen LH. Endothelin and the central and peripheral nervous systems:a decade of endothelin research [J]. Clin Exp Pharmacol Physiol,1999,26(12):980-984.
[87]Kuwaki T, Ling GY, Onodera M, et al. Endothelin in the central control of cardiovascular and respiratory functions [J]. Clin Exp Pharmacol Physiol,1999,26(12):989-994.
[88]Ryu JS, Shin CY, Yang SJ, et al. NMDA receptor and NO mediate ET-1-induced behavioral and cardiovascular effects in periaqueductal gray matter of rats [J]. Arch Pharm Res,2001,24 (1):64-8.
[89]Kastner S, Oertel MF, Scharbrodt W, et al. Endothelin-1 in plasma, cisternal CSF and microdialysate following aneurysmal SAH [J]. Acta Neurochir (Wien),2005, 147(12):1271-9; discussion 1279.
[90]Hoffman A, Keiser HR, Grossman E, et al. Endothelin concentrations in cerebrospinal fluid in depressive patients[J]. Lancet,1989,2(8678-8679):1519.
[91]Lampl Y, Fleminger G, Gilad R, et al. Endothelin in cerebrospinal fluid and plasma of patients in the early stage of ischemic stroke [J]. Stroke,1997,28(10):1951-1955.
[92]Goto K, Hama H, Kasuya Y. Molecular pharmacology and pathophysiological significance of endothelin [J]. Jpn J Pharmacol,1996,72(4):261-290.
[93]Gross PM, Weaver DF. A new experimental model of epilepsy based on the intraventricular injection of endothelin [J]. J Cardiovasc Pharmacol,1993,22 Suppl 8:S282-287.
[94]Nagasaka J, Tsuji M, Takeda H, et al. Role of endothelin receptor subtypes in the behavioral effects of the intracerebroventricular administration of endothelin-1 in conscious rats [J]. Pharmacol Biochem Behav,1999,64(1):171-176.
[95]Mateffyova A, Otahal J, Tsenov G, et al. Intrahippocampal injection of endothelin-1 in immature rats results in neuronal death, development of epilepsy and behavioral abnormalities later in life [J]. Eur J Neurosci,2006,24(2):351-60.
[96]梅麒,徐安定,廖卫平,等.海马内注射内皮素一1导致大鼠痫性发作和海马硬化的初步研究[J].中国神经精神疾病杂志,2009,35(05)：276-279.
[97]Shihara M, Hirooka Y, Hori N, et al. Endothelin-1 increases the neuronal activity and augments the responses to glutamate in the NTS [J]. Am J Physiol,1998,275(2 Pt 2):R658-665.
[98]黄怀宇,顾承志,王增辉,等.癫痫发作前后即刻血浆NO、ET_I浓度的研究[J].神经疾病与精神卫生,2002,2(05)：263-264.
[99]Xie JP, Wang XM, Wu XH. The value of serum endothelin for differential diagnosis of the decreased cerebral blood flow perfusion foci of epilepsy patients [J]. Sichuan Da Xue Xue Bao Yi Xue Ban,2004,35(1):80-82.
[100]Kraus GE, Bucholz RD, Yoon KW, et al. Cerebrospinal fluid endothelin-1 and endothelin-3 levels in normal and neurosurgical patients:a clinical study and literature review [J]. Surg.Neurol,1991,35(1):20-29.
[101]邬丽莎,张春来.马桑内酯癫痫大鼠脑内ET mRNA表达的改变[J].泸州医学院学报,2001,24(05)：373-375.
[102]徐安定,吴宜娟,苗海锋,等.内皮素一1诱导培养大鼠大脑皮质神经元凋亡的初步研究[J].中华神经医学杂志,2003,2(01)：45-47.
[103]Salom JB, Torregrosa G, Alborch E. Endothelins and the cerebral circulation [J]. Cerebrovasc Brain Metab Rev,1995,7(2):131-152.
[104]Schmidt-Ott KM, Xu AD, Tuschick S, et al. Hypoxia reverses dibutyryl-cAMP-induced stellation of cultured astrocytes via activation of the endothelin system [J]. FASEB J, 2001,15(7):1227-1229.
[105]Hama H, Kasuya Y, Sakurai T, et al. Role of endothelin-1 in astrocyte responses after acute brain damage [J]. J Neurosci Res,1997,7(6):590-602.
[106]肖争.癫痫模型研究进展[J].1998,27(5)：304-306.
[107]Morimoto K, Fahnestock M, Racine RJ. Kindling and status epilepticus models of epilepsy:rewiring the brain [J]. Prog Neurobiol,2004,73(1):1-60.
[108]Turski WA, Czuczwar SJ, Kleinrok Z, et al. Cholinomimetics produce seizures and brain damage in rats [J]. Experientia,1983,39(12):1408-1411.
[109]Turski WA, Cavalheiro EA, Schwarz M, et al. Limbic seizures produced by pilocarpine in rats:behavioural, electroencephalographic and neuropathological study [J]. Behav Brain Res,1983,9(3):315-335.
[110]Li GL, Xiao B, Xie GJ. Temporal lobe epilepsy model induced by pilocarpine in rats [J]. Hunan Yi Ke Da Xue Xue Bao,2003,28(1):29-32.
[111]Goffin K, Nissinen J, Van Laere K, et al. Cyclicity of spontaneous recurrent seizures in pilocarpine model of temporal lobe epilepsy in rat [J]. Exp Neurol,2007, 205(2):501-505.
[112]Mello LE, Cavalheiro EA, Tan AM, et al. Circuit mechanisms of seizures in the pilocarpine model of chronic epilepsy: cell loss and mossy fiber sprouting [J]. Epilepsia, 1993,34(6):985-995.
[113]Mathern GW, Babb TL, Leite JP, et al. The pathogenic and progressive features of chronic human hippocampal epilepsy [J]. Epilepsy Res,1996,26(1):151-161.
[114]Cavalheiro EA. The pilocarpine model of epilepsy [J]. Ital J Neurol Sci,1995, 16(1-2):33-37.
[115]Turski L, Ikonomidou C, Turski WA, et al. Review: cholinergic mechanisms and epileptogenesis. The seizures induced by pilocarpine:a novel experimental model of intractable epilepsy [J]. Synapse,1989,3(2):154-171.
[116]Dube C, Marescaux C, Nehlig A. A metabolic and neuropathological approach to the understanding of plastic changes that occur in the immature and adult rat brain during lithium-pilocarpine-induced epileptogenesis [J]. Epilepsia,2000,41 Suppl 6:S36-43.
[117]Dube C, Boyet S, Marescaux C, et al. Relationship between neuronal loss and interictal glucose metabolism during the chronic phase of the lithium-pilocarpine model of epilepsy in the immature and adult rat [J]. Exp Neurol,2001,167(2):227-241.
[118]Leite JP, Bortolotto ZA, Cavalheiro EA. Spontaneous recurrent seizures in rats:an experimental model of partial epilepsy [J]. Neurosci Biobehav Rev,1990,14(4):511-517.
[119]Cavalheiro EA, Leite JP, Bortolotto ZA, et al. Long-term effects of pilocarpine in rats: structural damage of the brain triggers kindling and spontaneous recurrent seizures [J]. Epilepsia,1991,32(6):778-782.
[120]Wieser HG. ILAE Commission Report. Mesial temporal lobe epilepsy with hippocampal sclerosis [J]. Epilepsia,2004,45(6):695-714.
[121]Chakir A, Fabene PF, Ouazzani R, et al. Drug resistance and hippocampal damage after delayed treatment of pilocarpine-induced epilepsy in the rat [J]. Brain Res Bull,2006, 71(1-3):127-138.
[122]Glien M, Brandt C, Potschka H, et al. Effects of the novel antiepileptic drug levetiracetam on spontaneous recurrent seizures in the rat pilocarpine model of temporal lobe epilepsy[J]. Epilepsia,2002,43(4):350-357.
[123]George Paxinos CW. The rat brain in stereotaxic coordinates (3rd edition) [M], Academic Press,1996.
[124]Racine RJ. Modification of seizure activity by electrical stimulation. Ⅱ. Motor seizure [J]. Electroencephalogr Clin Neurophysiol,1972,32(3):281-294.
[125]Glien M, Brandt C, Potschka H, et al. Repeated low-dose treatment of rats with pilocarpine:low mortality but high proportion of rats developing epilepsy [J]. Epilepsy Res,2001,46(2):111-119.
[126]Borges K, Gearing M, McDermott DL, et al. Neuronal and glial pathological changes during epileptogenesis in the mouse pilocarpine model [J]. Exp Neurol,2003, 182(1):21-34.
[127]Brunello AG, Weissenberger J, Kappeler A, et al. Astrocytic alterations in interleukin-6/Soluble interleukin-6 receptor alpha double-transgenic mice [J]. Am J Pathol,2000,157(5):1485-1493.
[128]Holmes GL, Sarkisian M, Ben-Ari Y, et al. Mossy fiber sprouting after recurrent seizures during early development in rats [J]. J Comp Neurol,1999,404(4):537-553.
[129]Holmes GL, Gairsa JL, Chevassus-Au-Louis N, et al. Consequences of neonatal seizures in the rat: morphological and behavioral effects [J]. Ann Neurol,1998,44(6):845-857.
[130]Hamilton SE, Loose MD, Qi M, et al. Disruption of the ml receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice [J]. Proc Natl Acad Sci U S A,1997,94(24):13311-13116.
[131]Smolders I, Khan GM, Manil J, et al. NMDA receptor-mediated pilocarpine-induced seizures:characterization in freely moving rats by microdialysis [J]. Br J Pharmacol, 1997,121(6):1171-1179.
[132]Meurs A, Clinckers R, Ebinger G, et al. Seizure activity and changes in hippocampal extracellular glutamate, GABA, dopamine and serotonin [J]. Epilepsy Res,2008, 78(1):50-59.
[133]Markram H, Segal M. Long-lasting facilitation of excitatory postsynaptic potentials in the rat hippocampus by acetylcholine [J]. J Physiol,1990,427:381-393.
[134]Smolders I, Bogaert L, Ebinger G, et al. Muscarinic modulation of striatal dopamine, glutamate, and GAB A release, as measured with in vivo microdialysis [J]. J Neurochem,' 1997,68(5):1942-1948.
[135]den Buuse M v, Webber KM. Endothelin and dopamine release [J]. Prog Neurobiol,2000, 60(4):385-405.
[136]Clinckers R, Smolders I, Meurs A, et al. Anticonvulsant action of hippocampal dopamine and serotonin is independently mediated by D and 5-HT receptors [J]. J Neurochem, 2004,89(4):834-843.
[137]谢建平,吴晓华.血浆内皮素水平对癫痫的诊断和鉴别诊断价值[J].四川大学学报(医学版),2004,35(01)：80-82.
[138]袁定新.海马硬化与癫痫[J].医学理论与实践,2007,20(05)：525-527.
[139]Morita H, Suzuki K, Mori N, et al. Occurrence of complement protein C3 in dying pyramidal neurons in rat hippocampus after systemic administration of kainic acid [J]. Neurosci Lett,2006,409(1):35-40.
[140]Monoghan DTC, C.W. Distribution of N-methyl-d-aspartatesensitive L-[3H] glutamate-binding sites in rat brain [J]. J Neurosci,1985,5:2909-2919.
[141]Sloviter RS, Sollas AL, Barbaro NM, et al. Calcium-binding protein (calbindin-D28K) and parvalbumin immunocytochemistry in the normal and epileptic human hippocampus [J]. J Comp Neurol,1991,308(3):381-96.
[142]孙殿荣.癫痫发病机制的研究进展[J].华西医学,2004,19(03)：524-525.
[143]Wasterlain CG, Shirasaka Y, Mazarati AM, et al. Chronic epilepsy with damage restricted to the hippocampus:possible mechanisms [J]. Epilepsy Res,1996,26(1):255-265.
[144]Johansen FF. Interneurons in rat hippocampus after cerebral ischemia. Morphometric, functional, and therapeutic investigations [J]. Acta Neurol Scand Suppl,1993,150:1-32.
[145]陈刚,邓艳春,王小木,等.癫痫大鼠海马神经元和星形胶质细胞的病理演变[J].中华神经外科疾病研究杂志,2007,6(03)：229-232.
[146]Tsenov G, Mateffyova A, Mares P, et al. Intrahippocampal injection of endothelin-1:a new model of ischemia-induced seizures in immature rats [J]. Epilepsia,2007,48 Suppl 5:7-13.
[147]Peredery O, Persinger MA, Parker G, et al. Temporal changes in neuronal dropout following inductions of lithium/pilocarpine seizures in the rat [J]. Brain Res,2000, 881(1):9-17.
[148]Magloczky Z, Freund TF. Delayed cell death in the contralateral hippocampus following kainate injection into the CA3 subfield [J]. Neuroscience,1995,66(4):847-860.
[149]Wang L, Liu YH, Huang YG, et al. Time-course of neuronal death in the mouse pilocarpine model of chronic epilepsy using Fluoro-Jade C staining [J]. Brain Res,2008, 1241:157-167.
[150]Houser CR, Miyashiro JE, Swartz BE, et al. Altered patterns of dynorphin immunoreactivity suggest mossy fiber reorganization in human hippocampal epilepsy [J]. J Neurosci,1990,10(1):267-282.
[151]Babb TL, Kupfer WR, Pretorius JK, et al. Synaptic reorganization by mossy fibers in human epileptic fascia dentate [J]. Neuroscience,1991,42(2):351-363.
[152]周铨,朱丹.颞叶癫痫患者海马硬化神经元脱失的亚群特点[J].中华神经医学杂志,2005,4(07)：677-679.
[153]Buckmaster PS, Jongen-Relo AL. Highly specific neuron loss preserves lateral inhibitory circuits in the dentate gyrus of kainate-induced epileptic rats [J]. J Neurosci,1999, 19(21):9519-9529.
[154]Briellmann RS, Kalnins RM, Berkovic SF, et al. Hippocampal pathology in refractory temporal lobe epilepsy:T2-weighted signal change reflects dentate gliosis [J]. Neurology, 2002,58(2):265-271.
[155]Vessal M, Dugani CB, Solomon DA, et al. Might astrocytes play a role in maintaining the seizure-prone state? [J]. Brain Res,2005,1044(2):190-196.
[156]Binder DK, Steinhauser C. Functional changes in astroglial cells in epilepsy [J]. Glia, 2006,54(5):358-368.
[157]Kang TC, Kim DS, Kwak SE, et al. Epileptogenic roles of astroglial death and regeneration in the dentate gyrus of experimental temporal lobe epilepsy [J]. Glia,2006, 54(4):258-271.
[158]Garzillo CL, Mello LE. Characterization of reactive astrocytes in the chronic phase of the pilocarpine model of epilepsy [J]. Epilepsia,2002,43 Suppl 5:107-109.
[159]Lee SH, Magge S, Spencer DD, et al. Human epileptic astrocytes exhibit increased gap junction coupling [J]. Glia,1995,15(2):195-202.
[160]Griffin WS, Yeralan O, Sheng JG, et al. Overexpression of the neurotrophic cytokine S100 beta in human temporal lobe epilepsy [J]. J Neurochem,1995,65(1):228-233.
[161]Penkowa M, Molinero A, Carrasco J, et al. Interleukin-6 deficiency reduces the brain inflammatory response and increases oxidative stress and neurodegeneration after kainic acid-induced seizures [J]. Neuroscience,2001,102(4):805-818.
[162]张秀丽.星型细胞在癫痫发病机制中作用的研究进展[J].国外医学.神经病学神经外科学分册,2001,28(01)：38-40.
[163]Nadler JV. The recurrent mossy fiber pathway of the epileptic brain [J]. Neurochem Res, 2003,28(11):1649-1658.
[164]Feng L, Molnar P, Nadler JV. Short-term frequency-dependent plasticity at recurrent mossy fiber synapses of the epileptic brain [J]. J Neurosci,2003,23(12):5381-5390.
[165]Wuarin JP, Dudek FE. Electrographic seizures and new recurrent excitatory circuits in the dentate gyrus of hippocampal slices from kainate-treated epileptic rats [J]. J Neurosci, 1996,16(14):4438-4448.
[166]Steward O. Reinnervation of dentate gyrus by homologous afferents following entorhinal cortical lesions in adult rats [J]. Science,1976,194(4263):426-428.
[167]Vezzani A, Civenni G, Rizzi M, et al. Enhanced neuropeptide Y release in the hippocampus is associated with chronic seizure susceptibility in kainic acid treated rats [J]. Brain Res,1994,660(1):138-143.
[168]Proper EA, Jansen GH, van VCW, et al. A grading system for hippocampal sclerosis based on the degree of hippocampal mossy fiber sprouting [J]. Acta Neuropathol,2001, 101(4):405-409.
[169]Okazaki MM, Evenson DA, Nadler JV. Hippocampal mossy fiber sprouting and synapse formation after status epilepticus in rats:visualization after retrograde transport of biocytin [J]. J Comp Neurol,1995,352(4):515-534.
[170]Cavazos JE, Zhang P, Qazi R, et al. Ultrastructural features of sprouted mossy fiber synapses in kindled and kainic acid-treated rats [J]. J Comp Neurol,2003, 458(3):272-292.
[171]Buckmaster PS, Zhang GF, Yamawaki R. Axon sprouting in a model of temporal lobe epilepsy creates a predominantly excitatory feedback circuit [J]. J Neurosci,2002, 22(15):6650-6658.
[172]Nadler JV, Okazaki MM, Gruenthal M, et al. Kainic acid seizures and neuronal cell death: insights from studies of selective lesions and drugs [J]. Adv Exp Med Biol,1986, 203:673-686.
[173]Post RM, Weiss SR. Convergences in course of illness and treatments of the epilepsies and recurrent affective disorders [J]. Clin EEG Neurosci,2004,35(1):14-24.
[174]李国良.海马苔藓纤维出芽与颞叶癫痫[J].国外医学(神经病学神经外科学分册),2002,29(06)：515-518.
[175]Lemos T, Cavalheiro EA. Suppression of pilocarpine-induced status epilepticus and the late development of epilepsy in rats [J]. Exp Brain Res,1995,102(3):423-428.
[176]Jessberger S, Romer B, Babu H, et al. Seizures induce proliferation and dispersion of doublecortin-positive hippocampal progenitor cells [J]. Exp Neurol,2005, 196(2):342-351.
[177]Anderson CM, Swanson RA. Astrocyte glutamate transport:review of properties, regulation, and physiological functions [J]. Glia,2000,32(1):1-14.
[178]Hinterkeuser S, Schroder W, Hager G, et al. Astrocytes in the hippocampus of patients with temporal lobe epilepsy display changes in potassium conductances [J]. Eur J Neurosci,2000,12(6):2087-2096.
[179]Barres BA, Barde Y. Neuronal and glial cell biology [J]. Curr Opin Neurobiol,2000, 10(5):642-648.