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Impact of the acute local inhibition of soluble epoxide hydrolase on diabetic skin microcirculatory dysfunction.
Diab Vasc Dis Res 2019; :1479164119860215DV

Abstract

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.

Authors+Show Affiliations

1 Université Grenoble Alpes, HP2 UMR INSERM 1042, Grenoble, France. 2 CHU Grenoble Alpes, Pôle Recherche, INSERM CIC1406, Grenoble, France.3 Department of Pharmacology, Rouen University Hospital, Rouen, France. 4 Laboratory of Pharmacokinetics, Toxicology and Pharmacogenetics, Rouen University Hospital, Rouen, France. 5 Normandie University, UNIROUEN, INSERM U1096, FHU REMOD-VHF, Rouen, France.6 Department of Galenic, Normandy University, UNIROUEN, Rouen, France. 7 INSERM U1239 Normandy University, UNIROUEN, Rouen, France.1 Université Grenoble Alpes, HP2 UMR INSERM 1042, Grenoble, France. 2 CHU Grenoble Alpes, Pôle Recherche, INSERM CIC1406, Grenoble, France.8 Department of Pathology, Henri Becquerel Center, Rouen, France.3 Department of Pharmacology, Rouen University Hospital, Rouen, France. 6 Department of Galenic, Normandy University, UNIROUEN, Rouen, France.6 Department of Galenic, Normandy University, UNIROUEN, Rouen, France. 7 INSERM U1239 Normandy University, UNIROUEN, Rouen, France.8 Department of Pathology, Henri Becquerel Center, Rouen, France.8 Department of Pathology, Henri Becquerel Center, Rouen, France.9 Department of Entomology and Cancer Center, University of California, Davis, CA, USA.9 Department of Entomology and Cancer Center, University of California, Davis, CA, USA.3 Department of Pharmacology, Rouen University Hospital, Rouen, France. 4 Laboratory of Pharmacokinetics, Toxicology and Pharmacogenetics, Rouen University Hospital, Rouen, France.1 Université Grenoble Alpes, HP2 UMR INSERM 1042, Grenoble, France. 2 CHU Grenoble Alpes, Pôle Recherche, INSERM CIC1406, Grenoble, France.3 Department of Pharmacology, Rouen University Hospital, Rouen, France. 5 Normandie University, UNIROUEN, INSERM U1096, FHU REMOD-VHF, Rouen, France.1 Université Grenoble Alpes, HP2 UMR INSERM 1042, Grenoble, France. 2 CHU Grenoble Alpes, Pôle Recherche, INSERM CIC1406, Grenoble, France.3 Department of Pharmacology, Rouen University Hospital, Rouen, France. 5 Normandie University, UNIROUEN, INSERM U1096, FHU REMOD-VHF, Rouen, France.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31267765

Citation

Savina, Yann, et al. "Impact of the Acute Local Inhibition of Soluble Epoxide Hydrolase On Diabetic Skin Microcirculatory Dysfunction." Diabetes & Vascular Disease Research, 2019, p. 1479164119860215.
Savina Y, Duflot T, Bounoure F, et al. Impact of the acute local inhibition of soluble epoxide hydrolase on diabetic skin microcirculatory dysfunction. Diab Vasc Dis Res. 2019.
Savina, Y., Duflot, T., Bounoure, F., Kotzki, S., Thiebaut, P. A., Serreau, P. A., ... Bellien, J. (2019). Impact of the acute local inhibition of soluble epoxide hydrolase on diabetic skin microcirculatory dysfunction. Diabetes & Vascular Disease Research, p. 1479164119860215. doi:10.1177/1479164119860215.
Savina Y, et al. Impact of the Acute Local Inhibition of Soluble Epoxide Hydrolase On Diabetic Skin Microcirculatory Dysfunction. Diab Vasc Dis Res. 2019 Jul 3;1479164119860215. PubMed PMID: 31267765.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Impact of the acute local inhibition of soluble epoxide hydrolase on diabetic skin microcirculatory dysfunction. AU - Savina,Yann, AU - Duflot,Thomas, AU - Bounoure,Frederic, AU - Kotzki,Sylvain, AU - Thiebaut,Pierre-Alain, AU - Serreau,Pierre-Alex, AU - Skiba,Mohamed, AU - Picquenot,Jean-Michel, AU - Cornic,Marie, AU - Morisseau,Christophe, AU - Hammock,Bruce, AU - Imbert,Laurent, AU - Cracowski,Jean-Luc, AU - Richard,Vincent, AU - Roustit,Matthieu, AU - Bellien,Jeremy, Y1 - 2019/07/03/ PY - 2019/7/4/entrez KW - Diabetes KW - skin microvascular dysfunction KW - soluble epoxide hydrolase KW - topical form SP - 1479164119860215 EP - 1479164119860215 JF - Diabetes & vascular disease research JO - Diab Vasc Dis Res N2 - 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. SN - 1752-8984 UR - https://www.unboundmedicine.com/medline/citation/31267765/Impact_of_the_acute_local_inhibition_of_soluble_epoxide_hydrolase_on_diabetic_skin_microcirculatory_dysfunction L2 - http://journals.sagepub.com/doi/full/10.1177/1479164119860215?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -