phenobarbital-sodium and Ischemic-Attack--Transient

Topics: Animals; Brain; Brain Injuries; Carboxypeptidases; Disease Models, Animal; Glutamate Carboxypeptidase II; Ischemic Attack, Transient; Kidney; Neuroprotective Agents; Organophosphorus Compounds; Protease Inhibitors

We describe here a new strategy for the treatment of stroke, through the inhibition of NAALADase (N-acetylated-alpha-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.

Topics: Animals; Brain Ischemia; Carboxypeptidases; Culture Techniques; Dipeptides; Disease Models, Animal; Drug Tolerance; Enzyme Inhibitors; Glutamate Carboxypeptidase II; Glutamic Acid; Ischemic Attack, Transient; Mice; Mice, Inbred ICR; Neuroprotective Agents; Organophosphorus Compounds; Rats; Rats, Sprague-Dawley; Stroke