Targeted Topical Antioxidant Therapy In Diabetic Wound Healing
Piul S. Rabbani, PhD, Alejandro Gomez-Viso, B.S, Joshua Cohen, B.S., Daniel J. Ceradini, MD.
New York University, New York, NY, USA.
PURPOSE: Currently no effective pharmacological agents exist for the treatment of chronic non-healing diabetic wounds. In prior work, 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), lose dose(LD)-NA or vehicle daily to 10mm-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 days vs 30 days in vehicle-treated wounds, with highest wound closure rate vs vehicle, p=0.0007. LD decreased pathologic healing time by 52% vs untreated wounds and by 41% vs vehicle. LD decreases wound burden 65% vs untreated, 48% vs vehicle, p<0.05. LD induces 72% ROS reduction in vivo, vs vehicle, p<0.01. HD does not significantly alter wound healing. Histologically, 10d-LD wounds showed least epithelial gap, 250% granulation tissue and 200% CD31+ vasculature, vs 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.
CONCLUSION: 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 development of NA for clinical application.
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