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

Research output: Contribution to journalArticle

246 Citations (Scopus)

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 1999
Externally publishedYes

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Brain Injuries
Glutamic Acid
Brain
Stroke
Excitatory Amino Acids
Middle Cerebral Artery Infarction
Nervous System Diseases
Neuropeptides
Rats
Hydrolysis
Ischemia
N-acetyl-1-aspartylglutamic acid
dipeptidase
Wounds and Injuries
Enzymes
2-(phosphonomethyl)pentanedioic acid

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Slusher, B. S., Vornov, J. J., Thomas, A. G., Hurn, P. D., Harukuni, I., Bhardwaj, A., ... 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

Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury. / Slusher, Barbara S.; Vornov, James J.; Thomas, Ajit G.; Hurn, Patricia D.; Harukuni, Izumi; Bhardwaj, Anish; Traystman, Richard J.; Robinson, Michael B.; Britton, Paul; Lu, X. C May; Tortella, Frank C.; Wozniak, Krystyna M.; Yudkoff, Marc; Potter, Beth M.; Jackson, Paul F.

In: Nature Medicine, Vol. 5, No. 12, 12.1999, p. 1396-1402.

Research output: Contribution to journalArticle

Slusher, BS, Vornov, JJ, Thomas, AG, Hurn, PD, Harukuni, I, Bhardwaj, A, Traystman, RJ, Robinson, MB, Britton, P, Lu, XCM, Tortella, FC, Wozniak, KM, Yudkoff, M, Potter, BM & Jackson, PF 1999, 'Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury', Nature Medicine, vol. 5, no. 12, pp. 1396-1402. https://doi.org/10.1038/70971
Slusher, Barbara S. ; Vornov, James J. ; Thomas, Ajit G. ; Hurn, Patricia D. ; Harukuni, Izumi ; Bhardwaj, Anish ; Traystman, Richard J. ; Robinson, Michael B. ; Britton, Paul ; Lu, X. C May ; Tortella, Frank C. ; Wozniak, Krystyna M. ; Yudkoff, Marc ; Potter, Beth M. ; Jackson, Paul F. / Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury. In: Nature Medicine. 1999 ; Vol. 5, No. 12. pp. 1396-1402.
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