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Foretinib Rescues Cutaneous Nerve Fibers in Experimental Diabetic Neuropathy
Simeon C. Daeschler, MD, Dr. med.1; Jennifer Zhang, B.Sc, MD, PhD2; Tessa Gordon, PhD3; Gregory Borschel, MD4; Konstantin Feinberg, PhD5
1SickKids Research Institute, Toronto, ON, Canada; 2The Hospital for Sick Children, Toronto, ON, Canada; 3Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada; 4Division of Plastic and Reconstructive Surgery, Riley Hospital for Children, Indianapolis, IN; 5IUPUI, Indianapolis, IN

Introduction: Diabetes is by far the most common cause of neuropathy, inducing neurodegeneration of terminal sensory nerve fibers associated with loss of sensation, paresthesia, and persistent pain. Presently available treatment strategies focus on pain control, yet unable to prevent or reduce nerve fiber loss in diabetic patients. Individuals with diabetic neuropathy are also very likely to be affected by chronic wound healing deficits, with incidence estimates ranging from 8-25%. A pan kinase inhibitor Foretinib prevents die-back degeneration in cultured sensory and sympathetic neurons in several pathological conditions by rescuing mitochondrial activity and has been proven safe in prospective clinical trials. Here we aimed at investigating a potential neuroprotective effect of Foretinib in experimental diabetic neuropathy.
Material & Methods: A mouse model of streptozotocin induced diabetes was used that expresses yellow fluorescent protein (YFP) in peripheral nerve fibers under the thy-1 promoter (n=20). These mice were block randomized in three experimental groups (n=10 Foretinib treatment, n=5 vehicle treatment, n=5 non-treated diabetic control). Five additional animals served as a non-diabetic control. Five weeks post diabetes induction terminal nerve fiber density in the plantar skin and cornea, as well as proximal nerve fiber morphology at the ankle and thigh level were compared between groups.
Results: Streptozotocin-injected mice developed a stable diabetic state (blood glucose > 270 mg/dl), with a significant reduction of corneal nerve fiber density by 33% to 57%, and intraepidermal nerve fiber density by 25% compared to the non-diabetic controls. When diabetic mice were treated with Foretinib, the dermal nerve fiber loss was significantly reduced compared to vehicle treated and non-treated diabetic mice. Nerve fiber morphology at the ankle and thigh level was not affected in this early disease stage.
Conclusion: Our results indicate a neuroprotective effect of Foretinib on cutaneous nerve fibers in experimental diabetic neuropathy. Our current research is focusing on: (i) performing the treatment on a genetic mouse model of diabetes in developmental and chronic stages of the disorder, aimed to examine the effect of Foretinib on preventing and reversing of the neuropathy (ii) optimization of Foretinibís dosage protocol, aimed to reduce the off-target effect of the drug and (iii) testing the effect of the treatment on the diabetic neuropathy-associated topical wound healing.


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