Vornov J J, Wozniak K, Lu M, Jackson P, Tsukamoto T, Wang E, Slusher B
Guilford Pharmaceuticals Inc., Baltimore, Maryland 21224, USA.
Ann N Y Acad Sci. 1999;890:400-5. doi: 10.1111/j.1749-6632.1999.tb08019.x.
Excessive glutamate receptor activation is thought to be involved in the neuronal injury caused by stroke. Based on the hypothesis that N-acetyl-aspartyl-glutamate (NAAG) is a modulatory neurotransmitter or storage form of glutamate, we have pursued a novel strategy of therapeutic intervention, blockade of N-acetylated alpha-linked acidic dipeptidase (NAALADase), the enzyme that hydrolyzes NAAG to liberate glutamate. Using the suture model of transient middle cerebral artery occlusion (MCAO) in rats, the prototype NAALADase inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) dramatically reduced extracellular glutamate accumulation measured by microdialysis both during a 2-hour occlusion and during reperfusion, consistent with an effect on glutamate supply. During reperfusion, the decrease in glutamate was accompanied by an equimolar, reciprocal rise in extracellular NAAG. NAALADase inhibition may prove to be a well tolerated therapy for cerebral ischemia. In addition, NAALADase inhibitors should prove to be important tools in understanding the physiological role of NAAG in the brain.
过量的谷氨酸受体激活被认为与中风引起的神经元损伤有关。基于N-乙酰天冬氨酰谷氨酸（NAAG）是一种调节性神经递质或谷氨酸储存形式的假设，我们采用了一种新的治疗干预策略，即阻断N-乙酰化α-连接酸性二肽酶（NAALADase），该酶可水解NAAG以释放谷氨酸。使用大鼠大脑中动脉短暂闭塞（MCAO）的缝合模型，原型NAALADase抑制剂2-（膦酰甲基）戊二酸（2-PMPA）在2小时闭塞期间和再灌注期间均显著降低了通过微透析测量的细胞外谷氨酸积累，这与对谷氨酸供应的影响一致。在再灌注期间，谷氨酸的减少伴随着细胞外NAAG等摩尔的反向增加。NAALADase抑制可能被证明是一种耐受性良好的脑缺血治疗方法。此外，NAALADase抑制剂应被证明是理解NAAG在大脑中生理作用的重要工具。
