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

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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.