GCPII (NAALADase) inhibition prevents long-term diabetic neuropathy in type 1 diabetic BB/Wor rats

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. Methods: 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. Results: 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. Conclusions: 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.