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

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 (2 R ,4 R )-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.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65724/1/j.1471-4159.2003.02321.x.pd

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

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.Ph.D.Biological SciencesHealth and Environmental SciencesNeurosciencesPublic healthUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/125614/2/3208421.pd