Effects of Systemic Chlorogenic Acid on Random-Pattern Dorsal Skin Flap Survival in Diabetic Rats

Abstract

There has been considerable interest in understanding the effects of antioxidants in flap survival during diabetes. Previous studies showed that chlorogenic acid (CGA) exhibits potent antioxidant effects. We aimed to determine the effects of systemic CGA treatment on skin flap survival in an experimental random-pattern dorsal skin flap model in diabetic rats. Twenty-eight male Wistar rats were divided into four groups: phosphate buffered saline (PBS)-treated or CGA-treated nondiabetic rats, PBS-treated or CGA-treated diabetic rats. Diabetes was induced by streptozotocin (45 mg/kg). Caudally based bipedicled dorsal skin flaps were elevated. CGA (100 mg/kg) or PBS (mL/kg; as vehicle) was administered intraperitoneally once daily. On postoperative day 7, flap survival, regional blood perfusion and microangiography were evaluated. The malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and nitric oxide (NO) levels were evaluated from the flap tissue. Capillary density and vascular endothelial growth factor (VEGF) expression were assessed. Harmful effects of diabetes on flap survival were observed. CGA attenuated these effects and allowed greater survival and blood perfusion. CGA decreased MDA and NO levels and increased GSH and SOD levels. CGA elevated capillary density and VEGF expression. This study showed that peripherally administered CGA significantly improved flap survival in diabetic and nondiabetic rats.Key words antioxidant; chlorogenic acid; diabetes; dorsal skin flap; flap survival; oxidative stress Skin flaps are widely used in the repair of local tissue loss and the reconstruction of several tissue defects. Flap necrosis is frequently observed in flap tissues in the postoperative period and is an unwanted effect of healing. Many factors are known to play a role in this major complication such as ischemia, inadequate blood flow and disturbed venous drainage.

Pharmacologic overview of systemic chlorogenic acid therapy on experimental wound healing

“…There has been a wide range of dosage for systemic administration of CGA, from 2.5 to 400 mg/kg (Hunyadi et al 2012;Karthikesan et al 2010a, b;Mubarak et al 2012;Yun et al 2012). However, systemic CGA treatment has antiinflammatory, analgesic, and flap-healing properties in vivo when used in the same dosage as in our study (Dos Santos et al 2006;Bagdas et al 2013Bagdas et al , 2014. In addition to systemic administration, long-term use of CGA has been studied to prove its bioactive capability in different models (Bagdas et al 2013(Bagdas et al , 2014Hunyadi et al 2012;Karthikesan et al 2010a, b).…”

“…The authors showed that topical application of CGA can accelerate the process of excision wound healing by its ability to increase collagen synthesis through upregulation of key players such as tumor necrosis factoralpha and transforming growth factor-beta1 during wound healing as well as by its anti-oxidant potential (Chen et al 2013). Similarly, topical or systematic CGA application in skin flap surgeries can accelerate healing and flap survival (Ashoori et al 1994;Bagdas et al 2014). Additionally, extracts from Turkish Scorzonera species, which contains high amounts of CGA, displayed wound-healing effect in incisional and excisional wound models (Kupeli Akkol et al 2011;Suntar et al 2012).…”

“…Biochemical analyses were performed as described in our previous report (Bagdas et al 2014). Wound tissue samples were rapidly collected after rats were sacrificed.…”

“…The tissue samples were embedded in paraffin wax, cut into 5 μm thick tissue sections, mounted on slides, and stained with hematoxylin-eosin (H&E). Each slide was examined semiquantitatively under a light microscope and graded as absent (−), slight (+), moderate (++), marked (+++), and extensive (++++) for capillary density, exudation, oedema, necrosis, infiltration of polymorphonuclear leukocytes (PMNL), proliferation of fibroblasts, and epithelization on ×200 power magnification, and average number of findings was noted as described before (Bagdas et al 2014). …”

“…In vivo wound healing effect of topical CGA treatment in excisional wound model has been projected recently (Chen et al 2013). Additionally, CGA may improve skin flap survival topically and systematically (Ashoori et al 1994;Bagdas et al 2014). …”