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

Ajit G. Thomas, Weilin Liu, Jennifer L. Olkowski, Zhaocheng Tang, Qian Lin, Xi Chun M. Lu, Barbara S. Slusher

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


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-βs. We hypothesized that GCP II inhibition could be neuroprotective also via TGF-βs, 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-β. To further assess the role of TGF-βs in 2-PMPA-mediated neuroprotection, a neutralizing antibody to TGF-β (TGF-β Ab) was used. In both in vitro and in vivo models of cerebral ischemia, TGF-β 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-β release.

Original languageEnglish (US)
Pages (from-to)33-40
Number of pages8
JournalEuropean Journal of Pharmacology
Issue number1
StatePublished - Oct 26 2001
Externally publishedYes


  • GCP II (glutamate carboxypeptidase)
  • Glutamate
  • Ischemia
  • Metabotropic glutamate receptor
  • NAAG (N-acetyl-aspartyl-glutamate)
  • NAALADase (N-acetylated alpha-linked acidic dipeptidase)
  • TGF-β (transforming growth factor-β)

ASJC Scopus subject areas

  • Pharmacology


Dive into the research topics of 'Neuroprotection mediated by glutamate carboxypeptidase II (NAALADase) inhibition requires TGF-β'. Together they form a unique fingerprint.

Cite this