Mice lacking glutamate carboxypeptidase II are protected from peripheral neuropathy and ischemic brain injury.
Excessive glutamate release is associated with neuronal damage. A new strategy for the treatment of neuronal injury involves inhibition of the neuropeptidase glutamate carboxypeptidase II (GCP II), also known as N-acetylated alpha-linked acidic dipeptidase. GCP II is believed to mediate the hydrolysis of N-acetyl-aspartyl-glutamate (NAAG) to glutamate and N-acetyl-aspartate, and inhibition of NAAG peptidase activity (by GCP II and other peptidases) is neuroprotective. Mice were generated in which the Folh1 gene encoding GCP II was disrupted (Folh1-/- mice). No overt behavioral differences were apparent between Folh1-/- mice and wild-type littermates, with respect to their overall performance in locomotion, coordination, pain threshold, cognition and psychiatric behavioral paradigms. Morphological analysis of peripheral nerves, however, showed significantly smaller axons (reduced myelin sheaths and axon diameters) in sciatic nerves from Folh1-/- mice. Following sciatic nerve crush, Folh1-/- mice suffered less injury and recovered faster than wild-type littermates. In a model of ischemic injury, the Folh1-/- mice exhibited a significant reduction (p < 0.05) in infarct volume compared with their wild-type littermates when subjected to middle cerebral artery occlusion, a model of stroke. These findings support the hypothesis that GCP II inhibitors may represent a novel treatment for peripheral neuropathies as well as stroke.
Bacich
Dean J
DJ
Department of Urology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Wozniak
Krystyna M
KM
Lu
X-C May
XC
O'Keefe
Denize S
DS
Callizot
Noelle
N
Heston
Warren D W
WD
Slusher
Barbara S
BS
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002545:Brain Ischemia / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004594:Electrophysiology; D043425:Glutamate Carboxypeptidase II / Q000172:deficiency* / Q000235:genetics*; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000473:pathology; D009409:Nerve Crush; D010523:Peripheral Nervous System Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D011597:Psychomotor Performance / Q000502:physiology; D012584:Sciatic Nerve / Q000473:pathology
D043425:Glutamate Carboxypeptidase II