Turski L, Cavalheiro E A, Schwarz M, Turski W A, De Moraes Mello L E, Bortolotto Z A, Klockgether T, Sontag K H
Brain Res. 1986 Apr 9;370(2):294-309. doi: 10.1016/0006-8993(86)90484-1.
Pilocarpine, given intraperitoneally to rats, reproduces the neuropathological sequelae of temporal lobe epilepsy and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain. In the present study, the effects of manipulating the activity of the gamma-aminobutyric acid (GABA)-mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats, were investigated. In animals pretreated with microinjections of isoniazid, 150 micrograms, an inhibitor of activity of the GABA-synthesizing enzyme, L-glutamic acid decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of pilocarpine, 100 and 200 mg/kg, resulted in severe motor limbic seizures and status epilepticus. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine-induced convulsions. Morphological analysis of frontal forebrain sections with light microscopy revealed seizure-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with pilocarpine in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of isoniazid did not augment seizures produced by pilocarpine, 200 mg/kg. Application of an irreversible inhibitor of GABA transaminase, gamma-vinyl-GABA (D,L-4-amino-hex-5-enoic acid), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of brain damage. Microinjections of gamma-vinyl-GABA, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of convulsions produced by pilocarpine, 380 mg/kg. The results demonstrate that the threshold for pilocarpine-induced seizures in rats is subjected to the regulation of the GABA-mediated synaptic inhibition within the substantia nigra.
给大鼠腹腔注射毛果芸香碱，可再现颞叶癫痫的神经病理学后遗症，并为研究惊厥活动的形成机制以及在前脑内癫痫发作的泛化和传播中起作用的途径提供了一个相关的动物模型。在本研究中，研究了操纵黑质内γ-氨基丁酸（GABA）介导的突触抑制活性对毛果芸香碱诱发大鼠癫痫发作的影响。在用150微克异烟肼（一种GABA合成酶L-谷氨酸脱羧酶的活性抑制剂）双侧微量注射到黑质网状部（SNR）预处理的动物中，非惊厥剂量的毛果芸香碱（100和200毫克/千克）导致严重的运动性边缘叶癫痫发作和癫痫持续状态。脑电图和行为监测显示，毛果芸香碱诱发惊厥的阈值显著降低。用光镜对额叶前脑切片进行形态学分析，发现海马结构、丘脑、杏仁核、嗅觉皮层、黑质和新皮层有与癫痫发作相关的损伤，这种损伤在毛果芸香碱剂量超过350毫克/千克时通常会观察到。双侧纹状体内注射异烟肼并没有增强200毫克/千克毛果芸香碱诱发的癫痫发作。将不可逆的GABA转氨酶抑制剂γ-乙烯基-GABA（D，L-4-氨基己-5-烯酸）5微克双侧注射到SNR中，可抑制380毫克/千克毛果芸香碱诱发的脑电图和行为性癫痫发作的出现。这种治疗也足以保护动物免受脑损伤的发生。将5微克γ-乙烯基-GABA双侧微量注射到背侧纹状体中，未能预防380毫克/千克毛果芸香碱诱发的惊厥发作。结果表明，大鼠中毛果芸香碱诱发癫痫发作的阈值受黑质内GABA介导的突触抑制的调节。
