Davis Center for Regenerative Biology and Medicine, MDI Biological Laboratory, Kathryn W. Davis Building 227, Old Bar Harbor Road, Salisbury Cove, ME 04672, USA.
School of Biology and Ecology, Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA.
J Diabetes Complications. 2018 Mar;32(3):249-257. doi: 10.1016/j.jdiacomp.2017.11.012. Epub 2017 Dec 6.
A complication of diabetes is neuropathy, a condition of sensory axon degeneration that originates in the epidermis. The mechanisms remain unknown but reactive oxygen species (ROS) have been implicated in this condition. In this study, we assessed the role of ROS and a candidate downstream target, MMP-13 in glucose-induced sensory axon degeneration in zebrafish and mice.
The effects of glucose on metabolism and sensory axon degeneration were assessed using qPCR and live imaging. ROS were analyzed using pentafluorobenzene-sulfonyl fluorescein and activation of the NF-κB stress response was determined using Tg(NF-κB:GFP) zebrafish. The role of MMP-13 and ROS in glucose-dependent axon degeneration was determined in zebrafish following treatment with the antioxidant, N-acetylcysteine and the MMP-13 inhibitor, DB04760. Neuropathic mice fed on a high-fat/high-sugar diet were treated with the MMP-13 inhibitor, CL-82198 to assess sensory recovery.
Glucose treatment of zebrafish induced metabolic changes that resemble diabetes. Sensory axon degeneration was mediated by ROS-induced MMP-13 and prevented upon antioxidant treatment or MMP-13 inhibition. MMP-13 inhibition also reversed neuropathy in diabetic mice.
We demonstrate that zebrafish are suitable to study glucose-induced neurotoxicity. Given the effects in zebrafish and mice, MMP-13 inhibition may be beneficial in the treatment of human diabetic neuropathy.
糖尿病的一种并发症是神经病变，这是一种感觉轴突退化的病症，起源于表皮。其机制尚不清楚，但活性氧（ROS）已被牵涉到这种情况中。在这项研究中，我们评估了 ROS 及其候选下游靶标 MMP-13 在葡萄糖诱导的斑马鱼和小鼠感觉轴突退化中的作用。
使用 qPCR 和活体成像评估葡萄糖对代谢和感觉轴突退化的影响。使用五氟苯磺酰荧光素分析 ROS，并用 Tg（NF-κB：GFP）斑马鱼测定 NF-κB 应激反应的激活。在用抗氧化剂 N-乙酰半胱氨酸和 MMP-13 抑制剂 DB04760 处理斑马鱼后，确定 MMP-13 和 ROS 在葡萄糖依赖性轴突退化中的作用。用 MMP-13 抑制剂 CL-82198 治疗高脂/高糖饮食喂养的神经病变小鼠，以评估感觉恢复情况。
葡萄糖处理斑马鱼诱导的代谢变化类似于糖尿病。感觉轴突退化是由 ROS 诱导的 MMP-13 介导的，并可通过抗氧化剂治疗或 MMP-13 抑制来预防。MMP-13 抑制也逆转了糖尿病小鼠的神经病变。
我们证明了斑马鱼适合研究葡萄糖诱导的神经毒性。鉴于在斑马鱼和小鼠中的作用，MMP-13 抑制可能有益于人类糖尿病性神经病变的治疗。
