Long Joseph B, Yourick Debra L, Slusher Barbara S, Robinson Michael B, Meyerhoff James L
Department of Polytrauma and Resuscitation Research, Division of Military Casualty Research, Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500, USA.
Eur J Pharmacol. 2005 Jan 31;508(1-3):115-22. doi: 10.1016/j.ejphar.2004.12.008. Epub 2005 Jan 7.
Glutamate carboxypeptidase (GCP) II (EC 3.4.17.21), which is also known as N-acetylated-alpha-linked acidic dipeptidase (NAALADase), hydrolyses the endogenous acidic dipeptide N-acetylaspartylglutamate (NAAG), yielding N-acetyl-aspartate and glutamate. Inhibition of this enzyme by 2-(phosphonomethyl) pentanedioic acid (2-PMPA) has been shown to protect against ischemic injury to the brain and hypoxic and metabolic injury to neuronal cells in culture, presumably by increasing and decreasing the extracellular concentrations of NAAG and glutamate, respectively. Since both NAAG and GCP II are found in especially high concentrations in the spinal cord, injuries to the spinal cord involving pathophysiological elevations in extracellular glutamate might be particularly responsive to GCP II inhibition. Lumbar subarachnoid injections of dynorphin A in rats cause ischemic spinal cord injury, elevated extracellular glutamate and a persistent hindlimb paralysis that is mediated through excitatory amino acid receptors. We therefore used this injury model to evaluate the protective effects of 2-PMPA. When coadministered with dynorphin A, 2-PMPA significantly attenuated the dynorphin A-induced elevations in cerebrospinal fluid glutamate levels and by 24 h postinjection caused significant dose-dependent improvements in motor scores that were associated with marked histopathological improvements. These results indicate that 2-PMPA provides effective protection against excitotoxic spinal cord injury.
谷氨酸羧肽酶（GCP）II（EC 3.4.17.21），也被称为N - 乙酰化 - α - 连接酸性二肽酶（NAALADase），可水解内源性酸性二肽N - 乙酰天冬氨酰谷氨酸（NAAG），生成N - 乙酰天冬氨酸和谷氨酸。已表明，2 - （膦酰甲基）戊二酸（2 - PMPA）对该酶的抑制作用可预防脑缺血损伤以及培养的神经元细胞的缺氧和代谢损伤，推测这分别是通过提高和降低细胞外NAAG和谷氨酸的浓度来实现的。由于NAAG和GCP II在脊髓中的浓度特别高，涉及细胞外谷氨酸病理生理升高的脊髓损伤可能对GCP II抑制特别敏感。向大鼠腰椎蛛网膜下腔注射强啡肽A会导致脊髓缺血性损伤、细胞外谷氨酸升高以及通过兴奋性氨基酸受体介导的持续性后肢麻痹。因此，我们使用这个损伤模型来评估2 - PMPA的保护作用。当与强啡肽A共同给药时，2 - PMPA显著减轻了强啡肽A诱导的脑脊液谷氨酸水平升高，并且在注射后24小时导致运动评分出现显著的剂量依赖性改善，这与明显的组织病理学改善相关。这些结果表明，2 - PMPA对兴奋性毒性脊髓损伤提供了有效的保护作用。
