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

Nature Medicine volume 5, pages 1396–1402 (1999)Cite this article

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.

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Figure 1: The NAALADase inhibitor 2-PMPA and a less-active analog 2-PMSA.
Figure 2: Protective effects of NAALADase inhibition in a cell culture model of cerebral ischemia.
Figure 3: Protective effect of NAALADase inhibition in a rat MCAO model of focal ischemia.
Figure 4: NAALADase inhibition alters glutamate and NAAG levels after MCAO.
Figure 5: Neurotoxicity of high affinity glutamate receptor blockade compared with NAALADase inhibition.

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Acknowledgements

The authors thank S. Snyder for his insight and discussions in the preparation of this manuscript and E. Lea and E. Lisska for their assistance in the amino-acid analyses. All experiments were supported by Guilford Pharmaceuticals.

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Authors and Affiliations

  1. Department of Research, Guilford Pharmaceuticals, Baltimore, 21224, Maryland, USA

    Barbara S. Slusher, James J. Vornov, Ajit G. Thomas, X.-C. May Lu, Krystyna M. Wozniak, Beth M. Potter & Paul F. Jackson

  2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    James J. Vornov, Ajit G. Thomas & Anish Bhardwaj

  3. Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Patricia D. Hurn, Izumi Harukuni & Richard J. Traystman

  4. Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, 19104-4318, Pennsylvania, USA

    Michael B. Robinson & Marc Yudkoff

  5. Division of Neurosciences, Walter Reed Army Institute of Research, Washington, DC, 20307-5100, USA

    Paul Britton & Frank C. Tortella

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  1. Barbara S. Slusher
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Correspondence to Barbara S. Slusher.

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Slusher, B., Vornov, J., Thomas, A. et al. Selective inhibition of NAALADase, which converts NAAG to glutamate, reduces ischemic brain injury. Nat Med 5, 1396–1402 (1999). https://doi.org/10.1038/70971

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