Glutamate carboxypeptidase II (NAALADase) inhibition as a novel therapeutic strategy

Ajit G. Thomas, Krystyna M. Wozniak, Takashi Tsukamoto, David Calvin, Ying Wu, Camilo Rojas, James Vornov, Barbara S. Slusher

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

GCP II inhibition decreases extracellular excitotoxic glutamate and increases extracellular NAAG, both of which provide neuroprotection. We have demonstrated with our potent and selective GCP II inhibitors efficacy in models of stroke, ALS and neuropathic pain. GCP II inhibition may have significant potential benefits over existing glutamate-based neuroprotection strategies. The upstream mechanism seems selective for excitotoxic induced glutamate release, as GCP II inhibitors in normal animals induced no change in basal glutamate. This suggestion has recently been corroborated by Lieberman and coworkers who found that both NAAG release and increase in GCP II activity appear to be induced by electrical stimulation in crayfish nerve fibers and that subsequent NAAG hydrolysis to glutamate contributes, at least in part, to subsequent NMDA receptor activation. Interestingly, even at relatively high doses of compounds, GCP II inhibition did not appear to be associated with learning/memory deficits in animals. Additionally, quantitative neurophysiological testing data and visual analog scales for 'psychedelic effects' in Phase I single dose and repeat dose studies showed GCP II inhibition to be safe and well tolerated by both healthy volunteers and diabetic patients. GCP II inhibition may represent a novel glutamate regulating strategy devoid of the side effects that have hampered the development of postsynaptic glutamate receptor antagonists.

Original languageEnglish (US)
Title of host publicationN-Acetylaspartate
Subtitle of host publicationA Unique Neuronal Molecule in the Central Nervous System
PublisherSpringer New York
Pages327-337
Number of pages11
ISBN (Print)9780387301716
DOIs
StatePublished - Jan 1 2006
Externally publishedYes

Publication series

NameAdvances in Experimental Medicine and Biology
Volume576
ISSN (Print)0065-2598

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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