Neuroscience and Mental Health Program, SickKids Research Institute, 686 Bay St, Toronto, ON, M5G 0A4, Canada.
Division of Plastic and Reconstructive Surgery, The Hospital for Sick Children, Toronto, ON, Canada.
Sci Rep. 2022 May 19;12(1):8444. doi: 10.1038/s41598-022-12455-3.
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. Foretinib prevents die-back degeneration in cultured sensory and sympathetic neurons 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. A mouse model of streptozotocin induced diabetes was used that expresses yellow fluorescent protein (YFP) in peripheral nerve fibers under the thy-1 promoter. Streptozotocin-injected mice developed a stable diabetic state (blood glucose > 270 mg/dl), with a significant reduction of intraepidermal nerve fiber density by 25% at 5 weeks compared to the non-diabetic controls. When diabetic mice were treated with Foretinib, a significantly greater volume of the cutaneous nerve fibers (67.3%) in the plantar skin was preserved compared to vehicle treated (37.8%) and non-treated (44.9%) diabetic mice while proximal nerve fiber morphology was not affected. Our results indicate a neuroprotective effect of Foretinib on cutaneous nerve fibers in experimental diabetic neuropathy. As Foretinib treated mice showed greater weight loss compared to vehicle treated controls, future studies may define more sustainable treatment regimen and thereby may allow patients to take advantage of this neuroprotective drug in chronic neurodegenerative diseases like diabetic neuropathy.
糖尿病是迄今为止最常见的周围神经病变的病因，导致与感觉丧失、感觉异常和持续性疼痛相关的末端感觉神经纤维的神经退行性变。Foretinib 通过挽救线粒体活性来防止培养的感觉和交感神经元的退行性变，并已在前瞻性临床试验中证明安全。在这里，我们旨在研究 Foretinib 在实验性糖尿病神经病变中的潜在神经保护作用。使用在 Thy-1 启动子下在周围神经纤维中表达黄色荧光蛋白 (YFP) 的链脲佐菌素诱导的糖尿病小鼠模型。链脲佐菌素注射的小鼠表现出稳定的糖尿病状态（血糖>270mg/dl），与非糖尿病对照组相比，5 周时表皮内神经纤维密度显著降低 25%。当糖尿病小鼠用 Foretinib 治疗时，与未治疗（44.9%）和未治疗（44.9%）糖尿病小鼠相比，足底皮肤中的皮肤神经纤维（67.3%）的体积明显更大，而近端神经纤维形态未受影响。我们的结果表明 Foretinib 对实验性糖尿病神经病变中的皮肤神经纤维具有神经保护作用。由于 Foretinib 治疗的小鼠与未治疗的对照组相比体重减轻更多，因此未来的研究可能会确定更可持续的治疗方案，从而使患者能够在慢性神经退行性疾病（如糖尿病神经病变）中受益于这种神经保护药物。
