Metabotropic glutamate receptor-mediated protection from glucose -induced oxidative injury in sensory neurons.

Abstract

The metabotropic glutamate receptors are G-protein coupled receptors with many cell signaling functions in the central and peripheral nervous systems. The type 3 metabotropic glutamate receptor (mGluR3) is particularly important to survival signaling, and has been implicated in a wide range of neurological disorders. Activating mGluR3 protects dorsal root ganglion neurons from glucose-induced oxidative injury by increasing antioxidant defenses. During hyperglycemia, oxidative injury and programmed cell death in dorsal root ganglion neurons underlies the formation and progression of diabetic sensory neuropathy. Using a rat embryo cell culture model of sensory neuropathy, the toxic effects of elevated glucose concentrations were examined in dorsal root ganglion neurons, and the neuroprotective potential of mGluR3-activating compounds was explored through 3 central hypotheses: (1) Does mGluR3 activation protect dorsal root ganglion neurons from glucose-induced cell death? (2) Does mGluR3 activation prevent glucose-induced oxidative injury? (3) Is mGluR3 neuroprotection mediated through increased glutathione antioxidant defense systems? Neurons exposed to excess glucose experienced oxidative damage, including reactive oxygen species accumulation, mitochondrial membrane depolarization, and programmed cell death. Initial experiments found that activating mGluR3 prevents oxidative damage, and that protection only occurs in neurons co-cultured with Schwann cells. Glial cells may facilitate synthesis of the antioxidant glutathione in neurons; subsequent experiments determined that activating mGluR3 increases glutathione concentration in both neurons and Schwann cells, and that protection requires glutathione synthesis. These results suggest that activating mGluR3 increases glutathione synthesis, thereby countering free radical production and glucose-induced oxidative damage in dorsal root ganglion neurons. Increasing endogenous antioxidant defenses in this manner is a potential therapeutic target for diabetic sensory neuropathy.