Metabotropic glutamate receptor 3 protects neurons from glucose‐induced oxidative injury by increasing intracellular glutathione concentration

High glucose concentrations cause oxidative injury and programmed cell death in neurons, and can lead to diabetic neuropathy. Activating the type 3 metabotropic glutamate receptor (mGluR3) prevents glucose-induced oxidative injury in dorsal root ganglion neurons co-cultured with Schwann cells. To determine the mechanisms of protection, studies were performed in rat dorsal root ganglion neuron-Schwann cell co-cultures. The mGluR3 agonist 2R,4R-4-aminopyrrolidine-2,4-dicarboxylate prevented glucose-induced inner mitochondrial membrane depolarization, reactive oxygen species accumulation, and programmed cell death, and increased glutathione (GSH) concentration in co-cultured neurons and Schwann cells, but not in neurons cultured without Schwann cells. Protection was diminished in neurons treated with the GSH synthesis inhibitor l-buthionine-sulfoximine, suggesting that mGluR-mediated protection requires GSH synthesis. GSH precursors and the GSH precursor GSH-ethyl ester also protected neurons from glucose-induced injury, indicating that GSH synthesis in Schwann cells, and transport of reaction precursors to neurons, may underlie mGluR-mediated neuroprotection. These results support the conclusions that activating glial mGluR3 protects neurons from glucose-induced oxidative injury by increasing free radical scavenging and stabilizing mitochondrial function, through increased GSH antioxidant defense.