Targeted Nrf2 activation therapy with RTA 408 enhances regenerative capacity of diabetic wounds

Aims: Though unmitigated oxidative stress in diabetic chronic non-healing wounds poses a major therapeutic challenge, currently, there are no effective pharmacological agents. We targeted the cytoprotective Nrf2/Keap1 pathway, which is dysfunctional in diabetic skin and the regenerative environment in the diabetic wound. We assessed the efficacy of a potent Nrf2-activator, RTA 408, a semi-synthetic oleanane triterpenoid, on accelerating diabetic wound healing. Methods: Using Lepr(db/db) mice, we made 10 mm-diameter excisional humanized wounds in dorsal skin. We administered RTA 408 formulations daily, and used ANOVA for comparison of time to closure, in vivo real-time ROS, histology, molecular changes. Results: We found that RTA 408, specifically a 0.1% formulation, significantly reduced wound healing time and increased wound closure rate. While either systemic or topical administration of RTA 408 is effective, wound closure time with the latter was far superior. RTA 408-treated diabetic wounds upregulated Nrf2 and downstream antioxidant genes, and exhibited well-vascularized granulation tissue that aided in re-epithelialization. Reintroduction of redox mechanisms via RTA 408-induced Nrf2 resulted in reduction of the oxidative status of wounds, to coordinate successful wound closure. Conclusions: This preclinical study shows that promoting Nrf2-mediated antioxidant activity in the localized regenerative milieu of a diabetic wound markedly improves the molecular and cellular composition of diabetic wound beds. RTA 408 treats and corrects the irregularity in redox balance mechanisms involving Nrf2, in an avenue not explored previously for treatment of diabetic wounds and tissue regeneration. Our study supports development of RTA 408 as a therapeutic modality for chronic diabetic wounds. (C) 2018 Elsevier B.V. All rights reserved.