A Dual-Acting Nitric Oxide Donor and Phosphodiesterase 5 Inhibitor Promotes Wound Healing in Normal Mice and Mice with Diabetes

Abstract

Chronic wounds affect a large percentage of the population worldwide and cause significant morbidity. Unfortunately, efficient compounds for the treatment of chronic wounds are yet not available. Endothelial dysfunction, which is at least in part a result of compromised nitric oxide production and concomitant reduction in cGMP levels, is a major pathologic feature of chronic wounds. Therefore, we designed and synthesized a compound with a unique dual-acting activity (TOP-N53), acting as a nitric oxide donor and phosphodiesterase 5 inhibitor, and applied it locally to full-thickness skin wounds in healthy and healing-impaired mice with diabetes. TOP-N53 promoted keratinocyte proliferation, angiogenesis, and collagen maturation in healthy mice without accelerating the wound inflammatory response or scar formation. Most importantly, it partially rescued the healing impairment of mice with genetically determined type II diabetes (db/db) by stimulating re-epithelialization and granulation tissue formation, including angiogenesis. In vitro studies with human and murine primary cells showed a positive effect of TOP-N53 on keratinocyte and fibroblast migration, keratinocyte proliferation, and endothelial cell migration and tube formation. These results demonstrate a remarkable healing-promoting activity of TOP-N53 by targeting the major resident cells in the wound tissue.