期刊
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
卷 4, 期 12, 页码 844-858出版社
WILEY
DOI: 10.1002/acn3.484
关键词
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资金
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institutes of Health [1R01DK10700701A1]
- Office of Research Development, Department of Veterans Affairs (Biomedical and Laboratory Research Service and Rehabilitation Research and Development) [101RX001030]
- American Diabetes Association (ADA)
- Mid Atlantic Nutrition Obesity Research Center, from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health [P30 DK072488]
- National Center for Research Resources [R24 RR017718]
- Office of Research Infrastructure Programs/OD from the National Institutes of Health [ROD012098A]
Objectives: There is a critical need to develop effective treatments for diabetic neuropathy. This study determined if a selective mGluR2/3 receptor agonist prevented or treated experimental diabetic peripheral neuropathy (DPN) through glutamate recycling and improved mitochondrial function. Methods: Adult male streptozotocin treated Sprague-Dawley rats with features of type 1 diabetes mellitus (T1DM) or Low Capacity Running (LCR) rats with insulin resistance or glucose intolerance were treated with 3 or 10 mg/kg/day LY379268. Neuropathy end points included mechanical allodynia, nerve conduction velocities (NCV), and intraepidermal nerve fiber density (IENFD). Markers of oxidative stress, antioxidant response, glutamate recycling pathways, and mitochondrial oxidative phosphorylation (OXPHOS) associated proteins were measured in dorsal root ganglia (DRG). Results: In diabetic rats, NCV and IENFD were decreased. Diabetic rats treated with an mGluR2/3 agonist did not develop neuropathy despite remaining diabetic. Diabetic DRG showed increased levels of oxidized proteins, decreased levels of glutathione, decreased levels of mitochondrial DNA (mtDNA) and OXPHOS proteins. In addition, there was a 20-fold increase in levels of glial fibrillary acidic protein (GFAP) and the levels of glutamine synthetase and glutamate transporter proteins were decreased. When treated with a specific mGluR2/3 agonist, levels of glutathione, GFAP and oxidized proteins were normalized and levels of superoxide dismutase 2 (SOD2), SIRT1, PGC-1 alpha, TFAM, glutamate transporter proteins, and glutamine synthetase were increased in DRG neurons. Interpretation: Activation of glutamate recycling pathways protects diabetic DRG and this is associated with activation of the SIRT1-PGC-1 alpha-TFAM axis and preservation of mitochondrial OXPHOS function.
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