TY - JOUR
T1 - Blockade of NAALADase
T2 - A novel neuroprotective strategy based on limiting glutamate and elevating NAAG
AU - Vornov, James J.
AU - Wozniak, Krystyna
AU - Lu, May
AU - Jackson, Paul
AU - Tsukamoto, Takashi
AU - Wang, Eric
AU - Slusher, Barbara
PY - 1999/1/1
Y1 - 1999/1/1
N2 - Excessive glutamate receptor activation is thought to be involved in the neuronal injury caused by stroke. Based on the hypothesis that N-acetylaspartyl-glutamate (NAAG) is a modulatory neurotransmitter or storage form of glutamate, we have pursued a novel strategy of therapeutic intervention, blockade of N-acetylated alpha-linked acidic dipeptidase (NAALADase), the enzyme that hydrolyzes NAAG to liberate glutamate. Using the suture model of transient middle cerebral artery occlusion (MCAO) in rats, the prototype NAALADase inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) dramatically reduced extracellular glutamate accumulation measured by microdialysis both during a 2-hour occlusion and during reperfusion, consistent with an effect on glutamate supply. During reperfusion, the decrease in glutamate was accompanied by an equimolar, reciprocal rise in extracellular NAAG. NAALADase inhibition may prove to be a well tolerated therapy for cerebral ischemia. In addition, NAALADase inhibitors should prove to be important tools in understanding the physiological role of NAAG in the brain.
AB - Excessive glutamate receptor activation is thought to be involved in the neuronal injury caused by stroke. Based on the hypothesis that N-acetylaspartyl-glutamate (NAAG) is a modulatory neurotransmitter or storage form of glutamate, we have pursued a novel strategy of therapeutic intervention, blockade of N-acetylated alpha-linked acidic dipeptidase (NAALADase), the enzyme that hydrolyzes NAAG to liberate glutamate. Using the suture model of transient middle cerebral artery occlusion (MCAO) in rats, the prototype NAALADase inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) dramatically reduced extracellular glutamate accumulation measured by microdialysis both during a 2-hour occlusion and during reperfusion, consistent with an effect on glutamate supply. During reperfusion, the decrease in glutamate was accompanied by an equimolar, reciprocal rise in extracellular NAAG. NAALADase inhibition may prove to be a well tolerated therapy for cerebral ischemia. In addition, NAALADase inhibitors should prove to be important tools in understanding the physiological role of NAAG in the brain.
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U2 - 10.1111/j.1749-6632.1999.tb08019.x
DO - 10.1111/j.1749-6632.1999.tb08019.x
M3 - Article
C2 - 10668445
AN - SCOPUS:0033403095
VL - 890
SP - 400
EP - 405
JO - Annals of the New York Academy of Sciences
JF - Annals of the New York Academy of Sciences
SN - 0077-8923
ER -