title: Diabetic neuropathic pain development in type 2 diabetic mouse model and the prophylactic and therapeutic effects of coenzyme Q10.
abstract: The early onset of type 2 diabetes mellitus (DM), driven by increasing obesity, is associated with peripheral neuropathy. Here, we characterize diabetic neuropathic pain in New Zealand obese diabetic mice (NZO/HILtJ) as a polygenic model of obesity with type 2 diabetes and investigate the role of coenzyme Q10 (CoQ10) in the prevention and treatment of diabetic neuropathic pain. Since the overexpression of mitogen-activated protein kinase (MAPK), nuclear factor-κB proteins (NF-Kb), toll-like receptor 4 (TLR4) and downstream cytokines (such as CCL2, CXCL10) are considered important factors contributing to the development of neuropathic pain, the expression of these factors and the inhibitory effects of CoQ10 were evaluated. NZO/HILtJ mice spontaneously developed type 2 DM and increased body mass with diabetic neuropathic pain. CoQ10 treatment decreased pain hypersensitivity and long-term supplementation prevented the development of diabetic neuropathic pain but did not attenuate diabetes. Spinal cord, blood serum, liver tissue, and dorsal root ganglia (DRG) from diabetic mice demonstrated increased lipid peroxidation, which was decreased by CoQ10 treatment. The percentage of positive neurons of p65 (the activated marker of NF-KB) and MAPK in DRG were significantly higher in DM mice compared to controls. However, CoQ10 treatment significantly decreased p65 and MAPK positive neurons in the DRG of DM mice. RT-PCR demonstrated that elevated levels of mRNA of CCL2, CXCL10 or TLR4 in the spinal cord of DM mice decreased significantly when DM mice were treated with CoQ10.
  
  
  CONCLUSIONS
  This model may be useful in understanding the mechanisms of neuropathic pain in type 2 DM induced neuropathic pain and may facilitate preclinical testing of therapies. CoQ10 may decrease oxidative stress in the central and peripheral nervous system by acting as an anti-oxidant and free-radical scavenger. These results suggest that CoQ10 might be a reasonable preventative strategy for long-term use and using CoQ10 treatment may be a safe and effective long-term approach in the treatment of diabetic neuropathy.
authors.affiliation: Department of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Yan Ping
authors.initials: YP
authors.lastname: Zhang
authors.forename: Chun Yu
authors.initials: CY
authors.lastname: Song
authors.forename: Yue
authors.initials: Y
authors.lastname: Yuan
authors.forename: Ariel
authors.initials: A
authors.lastname: Eber
authors.forename: Yiliam
authors.initials: Y
authors.lastname: Rodriguez
authors.forename: Roy C
authors.initials: RC
authors.lastname: Levitt
authors.forename: Peter
authors.initials: P
authors.lastname: Takacs
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yang
authors.forename: Ronald
authors.initials: R
authors.lastname: Goldberg
authors.forename: Keith A
authors.initials: KA
authors.lastname: Candiotti
mesh_terms: D000367:Age Factors; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications* / Q000517:prevention & control; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000209:etiology*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D010147:Pain Measurement; D017288:Pain Threshold / Q000187:drug effects; D011993:Recombinant Fusion Proteins; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014815:Vitamins / Q000627:therapeutic use*
chemical_list: D001786:Blood Glucose; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; D011993:Recombinant Fusion Proteins; C546114:TLR4 decoy; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014815:Vitamins; D014451:Ubiquinone; C024989:coenzyme Q10
keywords: Anti-oxidant; Coenzyme Q10; Neuropathic pain; Oxidative stress; Type 2 diabetes