Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury

Barbara S. Slusher, James J. Vornov, Ajit G. Thomas, Patricia D. Hurn, Izumi Harukuni, Anish Bhardwaj, Richard J. Traystman, Michael B. Robinson, Paul Britton, X. C.May Lu, Frank C. Tortella, Krystyna M. Wozniak, Marc Yudkoff, Beth M. Potter, Paul F. Jackson

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249 Scopus citations

Abstract

We describe here a new strategy for the treatment of stroke, through the inhibition of NAALADase (N-acetylated-α-linked-acidic dipeptidase), an enzyme responsible for the hydrolysis of the neuropeptide NAAG (N-acetyl- aspartyl-glutamate) to N-acetyl-aspartate and glutamate. We demonstrate that the newly described NAALADase inhibitor 2-PMPA (2- (phosphonomethyl)pentanedioic acid) robustly protects against ischemic injury in a neuronal culture model of stroke and in rats after transient middle cerebral artery occlusion. Consistent with inhibition of NAALADase, we show that 2-PMPA increases NAAG and attenuates the ischemia-induced rise in glutamate. Both effects could contribute to neuroprotection. These data indicate that NAALADase inhibition may have use in neurological disorders in which excessive excitatory amino acid transmission is pathogenic.

Original languageEnglish (US)
Pages (from-to)1396-1402
Number of pages7
JournalNature medicine
Volume5
Issue number12
DOIs
StatePublished - Dec 1 1999

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Slusher, B. S., Vornov, J. J., Thomas, A. G., Hurn, P. D., Harukuni, I., Bhardwaj, A., Traystman, R. J., Robinson, M. B., Britton, P., Lu, X. C. M., Tortella, F. C., Wozniak, K. M., Yudkoff, M., Potter, B. M., & Jackson, P. F. (1999). Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury. Nature medicine, 5(12), 1396-1402. https://doi.org/10.1038/70971