2-AMINO-7-PHOSPHONOHEPTANOIC ACID INHIBITS INSULIN-INDUCED CONVULSIONS AND STRIATAL ASPARTATE ACCUMULATION IN RATS WITH FRONTAL CORTICAL ABLATION
2-AMINO-7-PHOSPHONOHEPTANOIC ACID INHIBITS INSULIN-INDUCED CONVULSIONS AND STRIATAL ASPARTATE ACCUMULATION IN RATS WITH FRONTAL CORTICAL ABLATION
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DOI：
10.1111/j.1471-4159.1987.tb03403.x
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发表时间：
1987-07-01
影响因子：
4.7
通讯作者：
MELDRUM, BS
中科院分区：
文献类型：
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作者：
CHAPMAN, AG;ENGELSEN, B;MELDRUM, BS
兴奋性氨基酸拮抗剂2-氨基-7-膦庚酸(2-APH；0.5 mmol/kg，i.p.)防止胰岛素诱导的阵发性癫痫发作。38%的大鼠观察到完全保护，另外50%的大鼠观察到部分保护。额叶皮质消融损毁皮质纹状体通路导致受损的背侧新纹状体纹状体天冬氨酸(-28%)和谷氨酸(-18%)水平下降，纹状体谷氨酰胺水平升高(45%)，D-[~3H]天冬氨酸高亲和力摄取减少(-27%)。胰岛素诱导的低血糖导致完整纹状体内天冬氨酸水平(165%)急剧上升，谷氨酸(-20%)和谷氨酰胺(-38%)水平下降。用2-APH处理大鼠可显著逆转胰岛素引起的纹状体天冬氨酸、谷氨酸和谷氨酰胺水平的变化，尤其是在完整半球。在正常血糖对照组大鼠中，“代谢”，即受损半球的浓度，天冬氨酸池占72%，而“突触”，即完整和受损半球之间的浓度差，占整个纹状体天冬氨酸池的28%。2-APH对正常血糖大鼠纹状体内的“代谢性”天冬氨酸水平无影响，但几乎完全抑制“突触”天冬氨酸。在胰岛素诱导的低血糖后，“代谢”天冬氨酸池增加了一倍，而在没有2-APH的情况下，“突触”天冬氨酸池增加了3.5倍。胰岛素诱导的“突触”天冬氨酸水平上升几乎完全被2-APH阻断(上升5%，而不是上升3.5倍)。“代谢”天冬氨酸的周转率也受到2-APH的影响，但程度较小(存在时增加25%，而不存在2-APH时增加94%)。全身应用2-APH后纹状体二元酸水平的变化可以用皮质中2-APH阻断皮质纹状体通路的兴奋性输入的作用来最简单地解释。
Pretreatment of rats with the excitatory amino acid antagonist 2-amino-7-phosphonoheptanoic acid (2-APH; 0.5 mmol/kg, i.p.) protected against insulin-induced clonic seizures. Complete protection was observed in 38% of the rats and partial protection in an additional 50%. Lesioning of the corticostriatal pathway by frontal cortical ablation caused decreases in the striatal levels of aspartate (-28%) and glutamate (-18%), an increase in striatal glutamine level (45%), and decreased high-affinity uptake of D-[3H]aspartate (-27%) in the lesioned dorsal neostriatum. Insulin-induced hypoglycemia caused a predicted sharp increase in aspartate level (165%) and decreased glutamate (-20%) and glutamine (-38%) levels in the intact striatum. Pretreatment of rats with 2-APH significantly reversed the insulin-induced changes in striatal aspartate, glutamate, and glutamine levels, especially in the intact hemisphere. In normoglycemic control rats, the "metabolic," i.e., concentration in the lesioned hemisphere, aspartate pool constituted 72% and the "synaptic," i.e., the concentration difference between the intact and lesioned hemispheres, 28% of the total striatal aspartate pool. 2-APH had no effect on the level of "metabolic" aspartate in the striata of normoglycemic rats but caused an almost complete suppression of "synaptic" aspartate. Following insulin-induced hypoglycemia, the "metabolic" aspartate pool doubled, whereas the "synaptic" aspartate pool increased 3.5-fold in the absence of 2-APH. The insulin-induced rise in "synaptic" aspartate level was almost completely blocked by 2-APH (a 5% rise instead of a 3.5-fold rise). The turnover of "metabolic" aspartate also affected by 2-APH, but to a lesser extent (a 25% rise in the presence vs. a 94% rise in the absence of 2-APH). The striatal changes in levels of dicarboxylic acids after systemic 2-APH administration can be most simply explained in terms of an action of 2-APH in the cortex blocking excitatory inputs to the corticostriatal pathway.