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

Ben-Yehuda Greenwald, Maya; Tacconi, Carlotta; Jukic, Marko; Joshi, Natasha; Hiebert, Paul; Brinckmann, Jürgen; Tenor, Hermann; Naef, Reto; Werner, Sabine

Authors

Maya Ben-Yehuda Greenwald

Carlotta Tacconi

Marko Jukic

Natasha Joshi

Jürgen Brinckmann

Hermann Tenor

Reto Naef

Sabine Werner



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.

Citation

Ben-Yehuda Greenwald, M., Tacconi, C., Jukic, M., Joshi, N., Hiebert, P., Brinckmann, J., …Werner, S. (2021). A Dual-Acting Nitric Oxide Donor and Phosphodiesterase 5 Inhibitor Promotes Wound Healing in Normal Mice and Mice with Diabetes. Journal of Investigative Dermatology, 141(2), 415-426. https://doi.org/10.1016/j.jid.2020.05.111

Journal Article Type Article
Acceptance Date May 18, 2020
Online Publication Date Jun 27, 2020
Publication Date Feb 1, 2021
Deposit Date Feb 20, 2024
Journal Journal of Investigative Dermatology
Print ISSN 0022-202x
Electronic ISSN 1523-1747
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 141
Issue 2
Pages 415-426
DOI https://doi.org/10.1016/j.jid.2020.05.111
Public URL https://hull-repository.worktribe.com/output/4554030