GAMMA-VINYL GABA - COMPARISON OF NEUROCHEMICAL AND ANTICONVULSANT EFFECTS IN MICE
GAMMA-VINYL GABA - COMPARISON OF NEUROCHEMICAL AND ANTICONVULSANT EFFECTS IN MICE
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DOI：
10.1007/bf01243421
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发表时间：
1988-01-01
影响因子：
3.3
通讯作者：
SCHMUTZ, M
中科院分区：
文献类型：
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作者：
BERNASCONI, R;KLEIN, M;SCHMUTZ, M
γ-的生物化学和药理学作用乙烯基GABA（Vigabatrin，GVG）和4-氨基丁酸：2-酮戊二酸氨基转移酶的不可逆酶激活抑制剂（EC 2.6.1.19; GABA-T）。这种抗惊厥药产生了时间和剂量依赖性的GABA，苯丙氨酸和赖氨酸含量的升高皮层组织，同时降低谷氨酸，天冬氨酸和丙氨酸水平。此外，GVG引起谷氨酰胺浓度的双相变化（给药后1-4小时下降，20小时后增加）。此外，我们在脑中发现了一种新的尚未鉴定的氨基酸，其以与α-谷氨酰胺相同的保留时间洗脱。从HPLC阳离子交换柱分离氨基己二酸。注射药物后20小时，GVG大大增加了这种新化学实体的水平。在注射后1至60小时之间的所有测试间隔，GVG对最大电休克无效。GABA-T抑制剂剂量依赖性地保护小鼠免受异烟肼诱导的癫痫发作，同时引起脑GABA浓度增加。然而，这种明显的相关性仅适用于给药后4小时。为了更好地定义GVG的抗惊厥特性，在激发前1、2、4和24小时，用惊厥剂量的士的宁、戊四唑（PTZ）和印防己毒素处理小鼠组，并测量脑氨基酸水平，包括GVG的脑浓度。在所有情况下，GVG的抗惊厥作用和脑GABA水平增加的时间依赖性不同。仅用GVG处理的动物中的氨基酸浓度与给予GVG和化学惊厥剂的动物中的氨基酸浓度相似。GVG对GABA能神经传递受损引起的癫痫发作无选择性。虽然GVG是一种有效的GABA-T抑制剂，但它显然影响其他几种磷酸吡哆醛依赖性脑酶和/或与其他神经递质系统相互作用。
Biochemical and pharmacological effects of .gamma.-vinyl GABA (Vigabatrin, GVG), and irreversible enzyme-activated inhibitor of 4-aminobutyrate: 2-oxoglutarate aminotransferase (EC 2.6.1.19; GABA-T), were measured in mice. This anticonvulsant produced a time- and dose-dependent elevation of the GABA, phenylalanine and lysine contents of cortical tissue and simultaneously decreased glutamate, aspartate and alanine levels. In addition, GVG caused a biphasic change in glutamine concentrations (a decline 1-4 hours after administration, followed 20 hours later by an increase). Moreover, we found a new, as yet unidentified amino acid in the brain eluting with the same retention time as .alpha.-aminoadipic acid from an HPLC cation-exchange column. The level of this novel chemical entity was greatly increased by GVG 20 hours after injection of the drug. At all tested intervals between 1 and 60 hours after injection, GVG was ineffective against maximal electroshock. The GABA-T inhibitor dose-dependently protected mice against isoniazid-induced seizures, simultaneously causing an increase in brain GABA concentrations. However, this apparent correlation applied only until 4 hours after treatment. To better define the anticonvulsant profile of GVG, groups of mice were treated, 1, 2, 4, and 24 hours prior to challenge with convulsant doses of strychnine, pentetrazole (PTZ), and picrotoxin, and brain amino acid levels, including brain concentrations of GVG, were measured. In all instances, the time dependency of the anticonvulsant effects of GVG and of increases in brain GABA levels differed. Amino acid concentrations in animals treated only with GVG were similar to those in animals given GVG and a chemical convulsant. GVG showed no selectivity for seizures produced by impairment of GABA-ergic neurotransmission. Although GVG is an effective GABA-T inhibitor, it apparently affects several other pyridoxal-phosphate-dependent cerebral enzymes and/or interacts with other neurotransmitter systems as well.