Repurposing alagebrium for diabetic foot ulcer healing: Impact on AGEs/NFκB/NOX1 signaling

Diabetic foot ulcer (DFU) is a common diabetic complication associated with disability and reduced quality of life. Available therapeutics are not sufficient to combat the spread of DFU. Here we aim to investigate the impact of alagebrium, an advanced glycation end product (AGE)-crosslink breaker, on the healing of DFU. Diabetes was induced in Wistar rats by STZ, and after four weeks, wound was induced on the foot. Alagebrium (10 mg/kg) was administered orally for 14 days, and wound size was measured every 3 days. Behavioral tests i.e., hot plate and footprint tests, were performed to assess sensory function and gait. Blood was collected to assess HbA1c, serum AGEs, MDA and NOX1. Tissue was collected to assess histological changes and expression of NF-κB, iNOS, TNF-α, VEGF and EGF. In a subsequent set of experiments with similar design, alagebrium was applied topically as a film-forming gel. Systemic alagebrium treatment accelerated the healing of diabetic wound, improved sensory functions and gait, and ameliorated histological changes. It also reduced serum levels of AGEs, MDA and NOX1, and the tissue expression of NF-κB, iNOS, TNF-α, and increased VEGF and EGF in diabetic rats. Topical alagebrium led to similar beneficial effects i.e., accelerated diabetic wound healing, improved wound histological changes, reduced expression of NF-κB and iNOS and increased VEGF. Our findings suggest repurposing of alagebrium for the management of DFU to accelerate the healing process and improve the clinical outcomes in diabetic patients. [Display omitted]