Neuroprotection mediated by glutamate carboxypeptidase II (NAALADase) inhibition requires TGF-beta

Eur J Pharmacol. 2001 Oct 26;430(1):33-40. doi: 10.1016/s0014-2999(01)01239-0.


Inhibition of glutamate carboxypeptidase (GCP) II (EC, 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.

MeSH terms

  • Animals
  • Antibodies / pharmacology
  • Arterial Occlusive Diseases / prevention & control
  • Brain / blood supply
  • Brain / drug effects*
  • Brain / enzymology
  • Carboxypeptidases / antagonists & inhibitors*
  • Cells, Cultured
  • Cerebral Arteries / drug effects
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Glutamate Carboxypeptidase II
  • Neuroprotective Agents / pharmacology
  • Precipitin Tests
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Metabotropic Glutamate / drug effects
  • Transforming Growth Factor beta / analysis
  • Transforming Growth Factor beta / immunology
  • Transforming Growth Factor beta / pharmacology*


  • Antibodies
  • Enzyme Inhibitors
  • Neuroprotective Agents
  • Receptors, Metabotropic Glutamate
  • Transforming Growth Factor beta
  • Carboxypeptidases
  • Glutamate Carboxypeptidase II