Effect of SR58611A, a potent beta-3 adrenoceptor agonist, on cutaneous wound healing in diabetic and obese mice Paul Schaeffer a, ⁎ , André Bernat a , Michele Arnone b , Luciano Manara c , Jean-François Gallas d , Frédérique Dol-Gleizes a , Laurence Millet a , Alain Grosset a , Jean-Marc Herbert a a Cardiovascular Thrombosis Department, Sanofi-Synthélabo Recherche, 195 Route d'Espagne, 31036 Toulouse, France b Central Nervous System Department, Sanofi-Synthélabo Recherche, 195 Route d'Espagne, 31036 Toulouse, France c Sanofi-Synthelabo Recherche, via G.B. Piranesi, 38, 20137, Milan, Italy d Toxicology Department, Sanofi-Synthélabo Recherche, 371 Rue du Pr J Blayac 34184, Montpellier, France Received 20 September 2005; accepted 1 November 2005 Available online 1 December 2005 Abstract In diabetic patients, impairment of wound healing is a serious problem which represents a significant health burden. The effect of a highly selective beta-3 adrenoceptor agonist, SR58611A, on wound healing was assessed in animal models of type II diabetes. In db/db diabetic mice, a daily oral treatment with SR58611A (1, 3 and 10 mg/kg/day for two weeks) significantly reduced hyperglycaemia from 3 mg/kg/day onwards. The compound also normalized wound healing, starting from the lowest dose tested (1 mg/kg/day). SR58611A did not affect wound healing of control (lean) mice. An oral anti-diabetic agent, devoid of affinity for beta-3 adrenoceptors, troglitazone (130 mg/kg/day p.o.), normalized glycaemia but did not improve wound healing in db/db mice. Local application of SR58611A (200 μg/day in db/db mice) did not affect wound healing. SR58611A also normalized glucose levels in ob/ob mice, but only slightly improved wound healing in this strain. Moreover, in 17-week old db/db mice (i.e. severely insulin resistant) and in streptozotocin-induced diabetic mice, SR58611A slightly decreased hyperglycaemia and did not affect wound healing. In conclusion, SR58611A improves wound healing in animal models of non-insulin-dependent diabetes. This effect is not related to its effect on glucose levels, but probably implicates systemic effects of the compound. © 2005 Elsevier B.V. All rights reserved. Keywords: Beta-3 adrenoceptor; SR58611A; Diabetes; Wound healing; (Mice) 1. Introduction Obesity and type II diabetes (non-insulin-dependent diabe- tes mellitus, NIDDM) are of growing importance in our industrialized societies. In diabetic patients, impairment of wound healing is a serious problem which represents a sig- nificant health burden. For example, ulceration is the most common complication of diabetes that requires hospitalisation (Harding et al., 2002). Wound healing is a complex process which involves an interplay between epidermal and dermal cells, intracellular matrix, angiogenesis, plasma proteins and is governed by the local production of cytokines and growth factors (Singer and Clark, 1999; Harding et al., 2002). It has been suggested that diabetes impairs wound healing through disruption of local cytokine production, notably platelet de- rived growth factor (PDGF), tumor necrosis factor α (TNFα), interleukin-1β, and vascular endothelial growth factor (VEGF) (Frank et al., 1995; Doxey et al., 1998; Zykova et al., 2000). Animal models of diabetes are essential in order to deter- mine whether experimental compounds are able to improve various aspects of this pathology. The mutant C57BL/KsJ (db/db) diabetic mouse has emerged as a potentially relevant model of healing impairment (Greenhalgh et al., 1990; Tsuboi et al., 1992). Surgical wounds in these mice exhibit a marked delay as regards exudate inflammation, proliferation of granu- lation tissue, collagen synthesis and scarring (Greenhalgh et al., 1990). These diabetic mice develop type II diabetes syndrome (with hyperglycaemia, hyperinsulinemia, hypertriglyceridemia, European Journal of Pharmacology 529 (2006) 172 – 178 www.elsevier.com/locate/ejphar ⁎ Corresponding author. Thrombosis and Angiogenesis Department, Sanofi- Synthélabo Recherche, Sanofi-Aventis group, 195 Route d'Espagne, 31036 Toulouse, France. Tel.: +33 5 34 63 25 64; fax: +33 5 34 63 22 86. E-mail address: paul.schaeffer@sanofi-aventis.com (P. Schaeffer). 0014-2999/$ - see front matter © 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2005.11.005