Impact of the acute local inhibition of soluble epoxide hydrolase on diabetic skin microcirculatory dysfunction

• Published in: Diabetes & vascular disease research 2019-11, Vol.16 (6), p.523-529
• Main Authors: Savina, Yann, Duflot, Thomas, Bounoure, Frederic, Kotzki, Sylvain, Thiebaut, Pierre-Alain, Serreau, Pierre-Alex, Skiba, Mohamed, Picquenot, Jean-Michel, Cornic, Marie, Morisseau, Christophe, Hammock, Bruce, Imbert, Laurent, Cracowski, Jean-Luc, Richard, Vincent, Roustit, Matthieu, Bellien, Jeremy
• Format: Article
• Language: English
• Subjects: Administration, Cutaneous; Animals; Benzoates - administration & dosage; Biotechnology; Blood Flow Velocity; Cardiology and cardiovascular system; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - enzymology; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - physiopathology; Diabetic Angiopathies - enzymology; Diabetic Angiopathies - genetics; Diabetic Angiopathies - physiopathology; Diabetic Angiopathies - prevention & control; Disease Models, Animal; Enzyme Inhibitors - administration & dosage; Epoxide Hydrolases - antagonists & inhibitors; Epoxide Hydrolases - metabolism; Gels; Human health and pathology; Immunology; Life Sciences; Male; Mice, Inbred C57BL; Microcirculation - drug effects; Pharmaceutical sciences; Regional Blood Flow; Signal Transduction; Sus scrofa; Tissues and Organs; Urea - administration & dosage; Urea - analogs & derivatives
• ISSN: 1479-1641; 1752-8984
• DOI: 10.1177/1479164119860215

The impact of the local inhibition of soluble epoxide hydrolase, which metabolizes vasodilator and anti-inflammatory epoxyeicosanoids, on diabetic skin microvascular dysfunction was assessed. In diabetic db/db mice, basal skin blood flow assessed using laser Doppler imaging was similar to that of control mice, but thermal hyperemia was markedly reduced. At 2 h after the topical administration of an aqueous gel containing the soluble epoxide hydrolase inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB: 400 mg/L), the peak concentration of t-AUCB was detected in the skin of diabetic mice, which quickly decreased thereafter. In parallel, 2 h after application of t-AUCB treatment, thermal hyperemia was increased compared to the control gel. Quantification of t-AUCB in plasma of treated animals showed no or low systemic diffusion. Furthermore, haematoxylin and eosin histological staining of skin biopsies showed that skin integrity was preserved in t-AUCB-treated mice. Finally, for pig ear skin, a surrogate for human skin, using Franz diffusion cells, we observed a continuous diffusion of t-AUCB from 2 h after application to beyond 24 h. A single topical administration of a soluble epoxide hydrolase inhibitor improves microcirculatory function in the skin of db/db mice and might represent a new therapeutic approach for preventing the development of skin complications in diabetic patients.