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Systemic Antioxidant Therapy Enhances Regenerative Capacity Of Diabetic Skin
Piul S. Rabbani, PhD, Trevor Ellison, B.S., Camille Kim, B.S., Daniel J. Ceradini, MD.
New York University, New York, NY, USA.

Purpose: Diabetes-associated chronic non-healing wounds impose an overwhelming burden, where measures like glycemic control are insufficient to promote closure. We previously showed that the cytoprotective pathway, Nrf2-Keap1, is dysregulated in diabetes. When we restored antioxidant production, diabetic wound healing rates were accelerated. Here, we investigated whether oral Nrf2-induction(NI)-therapy promotes diabetic wound closure.
Methods. Using 10 week old Lepr-db/db mice, we made 10mm-diameter excisional wounds in dorsal skin. We gavaged the mice daily with vehicle, low dose (LD) or high dose (HD)-NI. We assessed wound time to closure, histological and molecular analysis of 10day-old wounds.
Results: LD-NI-oral-therapy reduced closure time to 23.3 days, vs 30 days with vehicle-therapy, p=0.0017. HD-NI-treated wounds heal in 26.83 days, non-significant vs vehicle-control. LD-NI decreased pathologic healing time by 42%, vs untreated wounds and vehicle-control, and decreased wound burden by 29%, p<0.05, vs untreated wounds, and by 42% compared to vehicle-treated wounds, p<0.05. LD-NI-therapy resulted in the fastest wound healing rate (log rank p=0.0008). H&E stains on 10d wound sections showed over 2-fold decrease in epithelial gap with LD-NI-therapy, vs vehicle-therapy, p<0.05. Granulation tissue area and CD31+ vasculature increased 5-fold and 1.5 fold, respectively with LD-NI-therapy. The antioxidant NQO1, downstream of Nrf2, was upregulated >3x with LD-NI-therapy, vs vehicle-therapy.
Conclusions: Cutaneous wound closure in diabetic mice is significantly reduced with oral LD-NI-therapy. LD-NI improves molecular and cellular composition of wound beds by upregulating Nrf2-mediated antioxidants. The data support advancement of NI as a therapeutic modality for chronic diabetic wounds.


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