Protection against glucose-induced neuronal death by NAAG and GCP II inhibition is regulated by mGluR3

Alison Berent-Spillson, Amanda M. Robinson, David Golovoy, Barbara Slusher, Camilo Rojas, James W. Russell

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


Glutamate carboxypeptidase II (GCP II) inhibition has previously been shown to be protective against long-term neuropathy in diabetic animals. In the current study, we have determined that the GCP II inhibitor 2-(phosphonomethyl) pentanedioic acid (2-PMPA) is protective against glucose-induced programmed cell death (PCD) and neurite degeneration in dorsal root ganglion (DRG) neurons in a cell culture model of diabetic neuropathy. In this model, inhibition of caspase activation is mediated through the group II metabotropic glutamate receptor, mGluR3. 2-PMPA neuroprotection is completely reversed by the mGluR3 antagonist (S)-α-ethylglutamic acid (EGLU). In contrast, group I and III mGluR inhibitors have no effect on 2-PMPA neuroprotection. Furthermore, we show that two mGluR3 agonists, the direct agonist (2R,4R)-4-aminopyrrolidine-2, 4-dicarboxylate (APDC) and N-acetyl-aspartyl-glutamate (NAAG) provide protection to neurons exposed to high glucose conditions, consistent with the concept that 2-PMPA neuroprotection is mediated by increased NAAG activity. Inhibition of GCP II or mGluR3 may represent a novel mechanism to treat neuronal degeneration under high-glucose conditions.

Original languageEnglish (US)
Pages (from-to)90-99
Number of pages10
JournalJournal of Neurochemistry
Issue number1
StatePublished - Apr 2004
Externally publishedYes


  • Apoptosis
  • Diabetes
  • Dorsal root ganglia
  • Glutamate carboxypeptidase II
  • Metabotropic glutamate receptor
  • N-acetyl-aspartyl-glutamate

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience


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