Zhang W, Slusher B, Murakawa Y, Wozniak K M, Tsukamoto T, Jackson P F, Sima A A F
Department of Pathology, Wayne State University, 540 E. Canfield Ave, Detroit, MI 48201, USA.
J Neurol Sci. 2002 Feb 15;194(1):21-8. doi: 10.1016/s0022-510x(01)00670-0.
AIMS/HYPOTHESIS: Hyperglutamatergic activity induced by ischemia is believed to underlie neuronal damage in a variety of neurological disorders, including neuropathic pain. Since ischemia is believed to be a prominent mechanism involved in diabetic polyneuropathy (DPN), we investigated the effect of the glutamate carboxypeptidase II (GCPII, EC #3.4-17.21; previously termed NAALADase), an enzyme responsible for the hydrolysis of the neuropeptide NAAG to NAA and glutamate, on the development of DPN in type 1 diabetic BB/Wor rats.
Diabetic animals were treated with 10 mg/kg/day i.p. of the selective GCPII inhibitor GPI-5232 from onset of diabetes for 6 months. Hyperalgesia to thermal stimulation and nerve conduction velocity (NCV) were measured monthly. The effect on structural DPN was assessed by scoring of single, teased myelinated fibers, myelinated fiber morphometry and ultrastructural examination of C-fibers at 6 months.
GCPII inhibition showed significant but partial effects on hyperalgesia (p<0.001), nerve conduction slowing (p<0.01) axonal and nodal structural changes (p<0.001), small myelinated fiber atrophy, and degenerative changes of C-fibers.
GCPII inhibition has beneficial effects on hyperalgesia, nerve function, and structural degenerative changes in DPN, which are likely mediated by inhibition of ischemia-induced glutamate release.
目的/假设：缺血诱导的高谷氨酸能活性被认为是包括神经性疼痛在内的多种神经系统疾病中神经元损伤的基础。由于缺血被认为是糖尿病性多发性神经病（DPN）的一个突出机制，我们研究了谷氨酸羧肽酶II（GCPII，EC编号3.4 - 17.21；以前称为N - 乙酰天门冬氨酰 - L - 丙氨酸二肽酶），一种负责将神经肽NAAG水解为NAA和谷氨酸的酶，对1型糖尿病BB/Wor大鼠DPN发展的影响。
糖尿病动物从糖尿病发病开始，每天腹腔注射10 mg/kg的选择性GCPII抑制剂GPI - 5232，持续6个月。每月测量对热刺激的痛觉过敏和神经传导速度（NCV）。6个月时通过对单根、 teased有髓纤维评分、有髓纤维形态计量学和C纤维超微结构检查评估对结构性DPN的影响。
GCPII抑制对痛觉过敏（p<0.001）、神经传导减慢（p<0.01）、轴突和结的结构变化（p<0.001）、小有髓纤维萎缩以及C纤维的退行性变化有显著但部分的影响。
GCPII抑制对DPN的痛觉过敏、神经功能和结构退行性变化有有益作用，这可能是通过抑制缺血诱导的谷氨酸释放介导的。
