Zhang W, Murakawa Y, Wozniak K M, Slusher B, Sima A A F
Department of Pathology, Wayne State University, Detroit, MI 48201, USA.
J Neurol Sci. 2006 Sep 25;247(2):217-23. doi: 10.1016/j.jns.2006.05.052. Epub 2006 Jun 15.
Excitotoxic glutamate release occurs in several neurological disorders. One source is derived from the hydrolysis of the neuropeptide N-acetyl aspartyl glutamate (NAAG) by glutamate carboxypeptidase II (GCPII, also known as NAALADase). Drugs that attenuate glutamate transmission have been shown to relieve neuropathic pain, however side effects have limited their clinical use. It appears that GCPII is exclusively recruited to provide a glutamate source in hyperglutamatergic, excitotoxic conditions and therefore would be devoid of such side effects. Here we report on the therapeutic effects of an orally bio-available GCP II inhibitor on established painful and sensory neuropathy in the spontaneously diabetic BB/Wor rat. It significantly improved hyperalgesia, nerve conduction velocity and underlying myelinated fiber atrophy. The data suggest that GCP II inhibition may provide a meaningful and effective approach to the treatment of painful diabetic neuropathy.
兴奋性毒性谷氨酸释放发生在多种神经系统疾病中。其中一个来源是由谷氨酸羧肽酶II（GCPII，也称为N-乙酰天门冬氨酰谷氨酸酶）水解神经肽N-乙酰天门冬氨酰谷氨酸（NAAG）产生的。已证明减弱谷氨酸传递的药物可缓解神经性疼痛，然而副作用限制了它们的临床应用。似乎GCPII仅在谷氨酸能亢进、兴奋性毒性的情况下被募集以提供谷氨酸来源，因此不会有此类副作用。在此，我们报告了一种口服生物可利用的GCP II抑制剂对自发性糖尿病BB/Wor大鼠已确立的疼痛性和感觉性神经病变的治疗效果。它显著改善了痛觉过敏、神经传导速度以及潜在的有髓纤维萎缩。数据表明，抑制GCP II可能为治疗疼痛性糖尿病神经病变提供一种有意义且有效的方法。
