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mGluR2/3 activation of the SIRT1 axis preserves mitochondrial function in diabetic neuropathy

mGluR2/3 activation of the SIRT1 axis preserves mitochondrial function in diabetic neuropathy

Authors :
Anjaneyulu Muragundla
Cheng-Ying Ho
Krish Chandrasekaran
James W. Russell
Joungil Choi
Neda Najimi
Gary Fiskum
Anmol Singh
Steven L. Britton
Tyler G. Demarest
Pranith Kumar
Lauren G. Koch
Avinash Rao Sagi
Source :
Annals of Clinical and Translational Neurology
Publication Year :
2017
Publisher :
Wiley, 2017.

Abstract

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-1α, 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-1α–TFAM axis and preservation of mitochondrial OXPHOS function.

Details

ISSN :
23289503
Volume :
4
Database :
OpenAIRE
Journal :
Annals of Clinical and Translational Neurology
Accession number :
edsair.doi.dedup.....2d0964c07f4f869d5aefcf524019dc44
Full Text :
https://doi.org/10.1002/acn3.484