title: Peripheral neuron plasticity is enhanced by brief electrical stimulation and overrides attenuated regrowth in experimental diabetes.
abstract: Peripheral nerve regrowth is less robust than commonly assumed, particularly when it accompanies common clinical scenarios such as diabetes mellitus. Brief extracellular electrical stimulation (ES) facilitates the regeneration of peripheral nerves in part through early activation of the conditioning injury response and BDNF. Here, we explored intrinsic neuronal responses to ES to identify whether ES might impact experimental diabetes, where regeneration is attenuated. ES altered several regeneration related molecules including rises in tubulin, Shh (Sonic hedgehog) and GAP43 mRNAs. ES was associated with rises in neuronal intracellular calcium but its strict linkage to regrowth was not confirmed. In contrast, we identified PI3K-PTEN involvement, an association previously linked to diabetic regenerative impairment. Following ES there were declines in PTEN protein and mRNA both in vitro and in vivo and a PI3K inhibitor blocked its action. In vitro, isolated diabetic neurons were capable of mounting robust responsiveness to ES. In vivo, ES improved electrophysiological and behavioral indices of nerve regrowth in a chronic diabetic model of mice with pre-existing neuropathy. Regrowth of myelinated axons and reinnervation of the epidermis were greater following ES than sham stimulation. Taken together, these findings identify a role for ES in supporting regeneration during the challenges of diabetes mellitus.
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, AB, T2N 4N1, Canada.
authors: B
authors: B
authors: Singh
authors: Division of Neurology, Department of Medicine, Neurosciences and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2B7, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, T2N 4N1, Canada.
authors: A
authors: A
authors: Krishnan
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, AB, T2N 4N1, Canada.
authors: I
authors: I
authors: Micu
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, AB, T2N 4N1, Canada.
authors: K
authors: K
authors: Koshy
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, AB, T2N 4N1, Canada.
authors: V
authors: V
authors: Singh
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, AB, T2N 4N1, Canada.
authors: J A
authors: JA
authors: Martinez
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, AB, T2N 4N1, Canada.
authors: D
authors: D
authors: Koshy
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, AB, T2N 4N1, Canada.
authors: F
authors: F
authors: Xu
authors: Division of Neurology, Department of Medicine, Neurosciences and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2B7, Canada.
authors: A
authors: A
authors: Chandrasekhar
authors: Electrical and Computer Engineering, University of Calgary, Calgary, AB, T2N 4N1, Canada.
authors: C
authors: C
authors: Dalton
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, AB, T2N 4N1, Canada.
authors: N
authors: N
authors: Syed
authors: Hotchkiss Brain Institute, University of Calgary, Calgary, AB, T2N 4N1, Canada.
authors: P K
authors: PK
authors: Stys
authors: Division of Neurology, Department of Medicine, Neurosciences and Mental Health Institute, University of Alberta, Edmonton, AB, T6G 2B7, Canada; Hotchkiss Brain Institute, University of Calgary, Calgary, AB, T2N 4N1, Canada. Electronic address: zochodne@ualberta.ca.
authors: D W
authors: DW
authors: Zochodne
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D004599:Electric Stimulation Therapy; D036386:Ephrin-A5 / Q000378:metabolism; D019922:GAP-43 Protein / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D009409:Nerve Crush; D009414:Nerve Growth Factors / Q000378:metabolism; D009416:Nerve Regeneration; D016501:Neurites / Q000378:metabolism; D009473:Neuronal Plasticity; D009474:Neurons / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D020127:Recovery of Function; D012584:Sciatic Nerve / Q000293:injuries; D015398:Signal Transduction; D013311:Streptozocin; D014404:Tubulin / Q000378:metabolism
chemical_list: D036386:Ephrin-A5; D019922:GAP-43 Protein; D053823:Hedgehog Proteins; D009414:Nerve Growth Factors; C465570:Shh protein, mouse; D014404:Tubulin; D013311:Streptozocin; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D002118:Calcium