PRS PSRC Podium Proofs 2016
Piul S. Rabbani, PhD, Alejandro Gomez-Viso, BS, Joshua Cohen, BS, Daniel J. Ceradini, MD
From the New York University, New York, N.Y.
PURPOSE: Currently, no effective pharmacological agents exist for the treatment of chronic nonhealing diabetic wounds. In previous study, we found dysfunctional Nrf2-Keap1 signaling in diabetic skin but restored the pathway to enhance wound healing. In this study, we assessed the efficacy of an Nrf2 activator (NA), hypothesizing that topical application accelerates diabetic wound healing.
METHODS: We topically administered high-dose (HD)-NA, lose-dose (LD)-NA, or vehicle daily to 10-mm diameter excisional humanized diabetic cutaneous wounds. We assessed wound time to closure, in vivo real-time ROS, and 10-day-old wounds for histological and molecular analysis.
RESULTS: LD-NA reduced healing time to 21.6 versus 30 days in vehicle-treated wounds, with highest wound closure rate versus vehicle, P = 0.0007. LD decreased pathologic healing time by 52% versus untreated wounds and by 41% versus vehicle. LD decreases wound burden 65% versus untreated, 48% versus vehicle, P < 0.05. LD induces 72% ROS reduction in vivo, versus vehicle, P < 0.01. HD does not significantly alter wound healing. Histologically, 10-day-old LD wounds showed least epithelial gap, 250% granulation tissue, and 200% CD31+ vasculature, versus vehicle, all P < 0.01. We found nuclear Nrf2 with NA, unlike vehicle. Both LD and HD upregulate Nrf2 target gene NQO1 by 6.5- and 10-fold, respectively, but do not affect MnSOD.
CONCLUSIONS: Topical LD-NA significantly decreases diabetic cutaneous wound healing time by altering the redox status of the wound bed through Nrf2-transcribed antioxidant genes. We demonstrate an effective strategy to treat chronic diabetic wounds and support the development of NA for clinical application.