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.
Berent-Spillson
Alison
A
Neuroscience Program, University of Michigan, Ann Arbor, Michigan, USA.
Russell
James W
JW
D000818:Animals; D000963:Antimetabolites / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D019328:Buthionine Sulfoximine / Q000633:toxicity; D002478:Cells, Cultured; D018920:Coculture Techniques; D003929:Diabetic Neuropathies / Q000378:metabolism / Q000503:physiopathology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D005947:Glucose / Q000378:metabolism / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism*; D006943:Hyperglycemia / Q000378:metabolism / Q000503:physiopathology; D042541:Intracellular Space / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism*; D012583:Schwann Cells / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D000963:Antimetabolites; D018690:Excitatory Amino Acid Agonists; D017382:Reactive Oxygen Species; D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3; D019328:Buthionine Sulfoximine; D005978:Glutathione; D005947:Glucose