Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Excessive glutamate receptor activation is thought to be involved in the neuronal injury caused by stroke. Based on the hypothesis that N-acetyl-aspartyl-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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PMID:Blockade of NAALADase: a novel neuroprotective strategy based on limiting glutamate and elevating NAAG. 1066 45

Inhibition of glutamate carboxypeptidase (GCP) II (EC 3.4.17.21), also termed N-acetylated alpha-linked acidic dipeptidase (NAALADase), has been shown to protect against ischemic injury presumably via decreasing glutamate and increasing N-acetyl-aspartyl-glutamate (NAAG). NAAG is a potent and selective mGlu3 receptor agonist. Activation of glial mGlu3 receptors has been shown to protect against NMDA toxicity by releasing transforming growth factors, TGF-betas. We hypothesized that GCP II inhibition could be neuroprotective also via TGF-betas, due to increased NAAG. To verify this, Enzyme-Linked Immunosorbent Assays (ELISAs) were performed on media from both control and ischemic cultures treated with the GCP II inhibitor, 2-(phosphonomethyl)-pentanedioic acid (2-PMPA). We found that 2-PMPA attenuated ischemia-induced declines in TGF-beta. To further assess the role of TGF-betas in 2-PMPA-mediated neuroprotection, a neutralizing antibody to TGF-beta (TGF-beta Ab) was used. In both in vitro and in vivo models of cerebral ischemia, TGF-beta Ab reversed the neuroprotection by 2-PMPA. Antibodies to other growth factors had no effect. Data suggests that neuroprotection by GCP II inhibition may be partially mediated by promoting TGF-beta release.
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PMID:Neuroprotection mediated by glutamate carboxypeptidase II (NAALADase) inhibition requires TGF-beta. 1169 60