Wound Healing Effects of Zofenopril and Fisetin in Rat Model of Diabetic Foot Ulcers

Abstract

Background: Diabetic foot ulcer (DFU) is a prevalent complication of diabetes. Current therapeutic options remain inadequate in controlling its progression. Objectives: To evaluate the wound-healing potential of zofenopril (ZOF) and fisetin (FS) in a rat model of DFU. Methods: Sixty-five rats were included in the study and divided into 7 groups: nDnW: non-diabetic, non-wounded; nDW: non-diabetic, wounded; DWC: diabetic, wounded control. Insulin, ZOF, FS, and ZOF+FS. Diabetes was induced using 60mg/kg streptozotocin (STZ), and a full-thickness excision wound was created on the dorsal surface of the hind paw. The wound size was measured by ImitoWound application. Assessment of blood glucose, C-reactive protein (CRP), interleukin-(IL)-10, total antioxidant capacity (TAOC), vascular endothelial growth factor (VEGF), and hydroxyproline was performed. Tissue samples were examined for histological changes. Results: ZOF, FS, and their combination significantly accelerated diabetic wound healing via reducing wound surface area and percentage of wound contraction, improved glycemic control, and mitigated histological alterations. They significantly reduced the serum level of CRP in the inflammatory phase and increased VEGF and hydroxyproline. Histopathological analysis revealed a reduction in inflammatory infiltration at the wound site, marked angiogenesis and fibroblast proliferation on Day 8, and moderate to excellent epidermal thickness with optimal collagen deposition on Day 16 post-wounding. Conclusions: ZOF, FS, and their combination enhanced wound healing by ameliorating inflammation, improving angiogenesis, collagen synthesis, and re-epithelization. The suggested mechanisms are anti-inflammatory, elevation of the level of VEGF and hydroxyproline, and glycemic control, thereby accelerating wound contraction and improving delayed wound healing in diabetes.