Abstract
Background: Small fiber neuropathy is a well-recognized complication of type 2 diabetes and has been shown to be responsible for both neuropathic pain and impaired wound healing. In previous studies, we have demonstrated that ganglioside GM3 depletion by knockdown of GM3 synthase fully reverses impaired wound healing in diabetic mice. However, the role of GM3 in neuropathic pain and small fiber neuropathy in diabetes is unknown. Purpose: Determine whether GM3 depletion is able to reverse neuropathic pain and small fibers neuropathy and the mechanism of the reversal. Results: We demonstrate that GM3 synthase knockout and the resultant GM3 depletion rescues the denervation in mouse footpad skin and fully reverses the neuropathic pain in diet-induced obese diabetic mice. In cultured dorsal root ganglia from diet-induced diabetic mice, GM3 depletion protects against increased intracellular calcium influx in vitro. Conclusions: These studies establish ganglioside GM3 as a new candidate responsible for neuropathic pain and small fiber neuropathy in diabetes. Moreover, these observations indicate that systemic or topically applied interventions aimed at depleting GM3 may improve both the painful neuropathy and the wound healing impairment in diabetes by protecting against nerve end terminal degeneration, providing a disease-modifying approach to this common, currently intractable medical issue.
Original language | English (US) |
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Journal | Molecular Pain |
Volume | 12 |
DOIs | |
State | Published - Aug 1 2016 |
Funding
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by NIAMS R21 NIH AR062898 and R01 NIH AR068375 (ASP), the Foglia Family Endowment, NIH 5R25NS070694-04 Research Education Program for Trainees in Neurology (DMM), the Dixon Young Investigator Grant: Northwestern Memorial Foundation (DMM), Cancer Center Support Grant (NCI CA060553), NIH K08 NS079482-01 (DMM), NIH 5R01DA013141-14 (RJM), and NIH/Rush University Medical Center 1R01AR064251-01 (RJM). Core support was provided by Northwestern’s Skin Disease Research Center (NIAMS P30AR057216), Mouse Histology and Phenotyping Laboratory (NCI CCSG P30CA060553), and Advanced Imaging Facility (NCI P30CA060553).
Keywords
- GM3 ganglioside
- Neuropathic pain
- diabetes
- glucose intolerance
- obesity
- small fiber neuropathy
ASJC Scopus subject areas
- Anesthesiology and Pain Medicine
- Cellular and Molecular Neuroscience
- Molecular Medicine