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

We describe here a new strategy for the treatment of stroke, through the in hibition of NAALADase (N-acetylated-alpha-linked-acidic dipeptidase), an en zyme responsible for the hydrolysis of the neuropeptide NAAG (N-acetyl-aspa rtyl-glutamate) to N-acetyl-aspartate and glutamate. We demonstrate that th e newly described NAALADase inhibitor 2-PMPA (2-(phosphonomethyl)pentanedio ic acid) robustly protects against ischemic injury in a neuronal culture mo del of stroke and in rats after transient middle cerebral artery occlusion. Consistent with inhibition of NAALADase, we show that 2-PMPA increases NAA G and attenuates the ischemia-induced rise in glutamate. Both effects could contribute to neuroprotection. These data indicate that NAALADase inhibiti on may have use in neurological disorders in which excessive excitatory ami no acid transmission is pathogenic.