157. Dietary Supplementation With 4-aminopyridine (4AP) to Promote Enhanced Wound Healing in Type II Diabetes

PURPOSE: Impaired wound healing is a serious complication of type 2 diabetes, often resulting in chronic ulcers, infections, and, in severe cases, amputation. Previous research has demonstrated that 4-Aminopyridine (4AP), a potassium channel blocker, accelerates wound healing in non-diabetic models by promoting nerve growth and tissue regeneration. This study investigates the efficacy of 4AP in enhancing wound healing in a murine model of type 2 diabetes, hypothesizing that it will accelerate wound closure and improve overall healing outcomes in diabetic wounds. METHODS: Type 2 diabetes was induced in wild-type C57BL/6J mice (n = 20) by feeding a high-fat diet for 12 weeks to model the metabolic impairments associated with diabetes, including impaired wound healing. After diabetes was established, the mice were randomized into two treatment groups: the 4AP group (3 mM) and a phosphate-buffered saline (PBS) control group (n = 10 per group). Treatment with 4AP or PBS continued for an additional 2 weeks. Following the treatment period, two symmetrical full-thickness wounds (6 mm in diameter) were created on the dorsal surface of each mouse using a sterile biopsy punch. To better simulate human wound healing and prevent wound contraction, a silicone splint was applied around each wound. Wound healing was monitored daily via digital photography, and wound areas were measured to track closure over a 16-day period. The percentage of wound healing was calculated at each post-operative day (POD). Statistical analyses were conducted using Welch’s two-sample t-tests to assess differences in wound closure between groups, with a p-value of <0.05 considered significant. RESULTS: Mice treated with 4AP showed significantly faster wound closure compared to the PBS control group, with significant differences emerging as early as POD 2. On POD 2, 4AP-treated mice exhibited 25.5% wound closure compared to 17% in the PBS group (p = 0.0213). By POD 3, the 4AP group achieved 40.2% wound closure, significantly higher than the PBS group’s 29.5% (p = 0.0176). This trend continued through POD 7, with the 4AP group showing 85% wound closure compared to 70% in the PBS group (p = 0.0059). By POD 9, the 4AP-treated mice achieved 93.7% wound closure, while the PBS group reached 83.2% (p = 0.0067). By POD 11, the 4AP group had nearly complete wound closure at 99%, whereas the PBS group showed 90% closure (p = 0.0421). Significant differences in wound closure persisted through POD 11, after which both groups approached complete wound closure, with no significant differences observed at POD 14 and POD 16. CONCLUSION: The results demonstrate that 4AP significantly accelerates wound healing in a murine model of type 2 diabetes, with faster wound closure rates compared to PBS-treated controls. The 4AP treatment led to earlier wound healing, a higher percentage of wound closure, and greater consistency across individual mice. These findings suggest that 4AP may hold promise as a novel therapeutic agent for diabetic wound healing, addressing a critical unmet need in this patient population.