GCPII (NAALADase) inhibition prevents long-term diabetic neuropathy in type 1 diabetic BB/Wor rats.
OBJECTIVE
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.
Zhang
W
W
Department of Pathology, Wayne State University, 540 E. Canfield Ave, Detroit, MI 48201, USA.
Slusher
B
B
Murakawa
Y
Y
Wozniak
K M
KM
Tsukamoto
T
T
Jackson
P F
PF
Sima
A A F
AA
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D043425:Glutamate Carboxypeptidase II; D005977:Glutarates / Q000627:therapeutic use*; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D006943:Hyperglycemia / Q000209:etiology; D008297:Male; D009412:Nerve Fibers / Q000187:drug effects / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000473:pathology; D009431:Neural Conduction / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D011480:Protease Inhibitors / Q000627:therapeutic use*; D051381:Rats; D011913:Rats, Inbred BB; D012584:Sciatic Nerve / Q000503:physiopathology; D005464:Fluorobenzenes; D005466:Fluorocarbons
D002268:Carboxypeptidases; D043425:Glutamate Carboxypeptidase II; D005977:Glutarates; D011480:Protease Inhibitors; C436737:(2-((pentafluorophenylmethyl)hydroxyphosphinyl) methyl)pentanedioic acid; D005464:Fluorobenzenes; D005466:Fluorocarbons