UFP-101 alleviates diabetic peripheral neuropathy through membrane metallo-endopeptidase

Diabetic peripheral neuropathy (DPN) the most common chronic complication in type 1 and type 2 diabetes due to metabolic dysregulation and nerve ischemia. affects 19-34 % of diabetic patients with limited treatment options. This research aimed to explore the therapeutic potential of UFP-101, a nociceptible/orphanin FQ-N/OFQ receptor (NOPR) antagonist, in DPN. Thirty male Sprague - Dawley rats were divided into five groups: control, DPN model, and three DPN groups treated with different doses of UFP-101 (0.01 mg/kg, 0.03 mg/kg, 0.1 mg/kg). Human umbilical vein endothelial cells were also split into six groups with different treatments related to glucose levels, N/OFQ, UFP-101, and inhibitors. High-dose UFP-101 (0.03 mg/kg and 0.1 mg/kg) had positive effects. It Reduced tail sensitivity, reduced sciatic nerve stimulation thresholds, and restored femoral artery blood flow. Molecularly, it downregulated PKC phosphorylation, decreased MME protein expression, increased serum CNP levels, and improved nerve fiber integrity. In cell culture, Go6976 and LCZ696 reduced MME expression, and UFP - 101, Go6976, and LCZ696 increased CNP levels. UFP-101 alleviates DPN progression by regulating PKC-MME-CNP signal axis, indicating that it may become the first DPN disease targeted therapy.