title: Neuroprotection mediated by glutamate carboxypeptidase II (NAALADase) inhibition requires TGF-beta.
abstract: 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.
authors.affiliation: Guilford Pharmaceuticals Inc., 6611 Tributary Street, Baltimore, MD 21224, USA.
authors.forename: A G
authors.initials: AG
authors.lastname: Thomas
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.forename: J L
authors.initials: JL
authors.lastname: Olkowski
authors.forename: Z
authors.initials: Z
authors.lastname: Tang
authors.forename: Q
authors.initials: Q
authors.lastname: Lin
authors.forename: X C
authors.initials: XC
authors.lastname: Lu
authors.forename: B S
authors.initials: BS
authors.lastname: Slusher
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001157:Arterial Occlusive Diseases / Q000517:prevention & control; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D043425:Glutamate Carboxypeptidase II; D018696:Neuroprotective Agents / Q000494:pharmacology; D011233:Precipitin Tests; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000276:immunology / Q000494:pharmacology*
chemical_list: D000906:Antibodies; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D018094:Receptors, Metabotropic Glutamate; D016212:Transforming Growth Factor beta; D002268:Carboxypeptidases; D043425:Glutamate Carboxypeptidase II