Abstract
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 language | English (US) |
---|---|
Pages (from-to) | 90-99 |
Number of pages | 10 |
Journal | Journal of Neurochemistry |
Volume | 89 |
Issue number | 1 |
DOIs | |
State | Published - Apr 2004 |
Externally published | Yes |
Keywords
- Apoptosis
- Diabetes
- Dorsal root ganglia
- Glutamate carboxypeptidase II
- Metabotropic glutamate receptor
- N-acetyl-aspartyl-glutamate
ASJC Scopus subject areas
- Biochemistry
- Cellular and Molecular Neuroscience