Research Article| Volume 60, ISSUE 5, P563-568, May 2007

Beneficial effects of caffeic acid phenethyl ester (CAPE) on the ischaemia-reperfusion injury in rat skin flaps



      Reperfusion injury is a phenomenon that occurs when tissues are subjected to ischaemia for a variable period of time, after which they are reperfused. Many factors have been implicated in the cause of reperfusion injury including free radicals and neutrophils. Caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE) is an active component of propolis from honeybee; it has anti-inflammatory and immunomodulatory properties, and protective effects against ischaemia-reperfusion (I/R) injury. We investigated the effects of CAPE on the survival of skin flaps in the rat.

      Materials and methods

      Eighteen Wistar rats were used, and randomly divided into three groups (n=6 rats each group): the control group (Group 1), ethanol group (Group 2), and CAPE group (Group 3). A caudally based rectangular flap, 3×10 cm in size, was elevated on the back of the rat, according to the method described by Khouri and colleagues. The flap was sutured back into its original place. In the control group, saline 0.2 ml/day was given intraperitoneally (i.p.). Five percent ethanol 0.2 ml/day was administered i.p. in the ethanol group, and CAPE 50 μmol/kg/day i.p. in the CAPE group. To observe the effects of CAPE, levels of malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH), glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) were measured from extracted skin tissue. Flap viability was evaluated seven days after the initial operation, measuring necrotic areas of flaps and total flap areas.


      MDA and NO levels were significantly decreased in CAPE group; and however, GSH, GSH-Px, and SOD enzyme activities were significantly increased in CAPE group.
      We believed that the CAPE had beneficial effects to improve the survival of skin flaps since it has antioxidative and anti-inflammatory properties, and protective effects against I/R injury.


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        • Reilly P.M.
        • Schiller H.J.
        • Bulkley G.B.
        Pharmacologic approach to tissue injury mediated by free-radicals and other reactive oxygen metabolites.
        Am J Surg. 1991; 161: 488-503
        • Cordeiro P.G.
        • Mastorakos D.P.
        • Hu Q.-Y.
        • et al.
        The protective effect of l-arginine on ischemia-reperfusion injury in rat skin flaps.
        Plast Reconstr Surg. 1997; 100: 1227-1233
        • Askar I.
        • Bozkurt M.
        Protective effects of immunosuppressants and steroids against ischemia-reperfusion injury in cremaster muscle flap at microcirculatory level.
        Microsurgery. 2002; 22: 361-366
        • Cordeiro P.G.
        • Lee J.J.
        • Mastorakos D.
        • et al.
        Prevention of ischemia-reperfusion injury in a rat skin flap model: the role of mast cells, cromolyn sodium, and histamine receptor blockade.
        Plast Reconstr Surg. 2000; 105: 654-659
        • Akamatsu J.
        • Ueda K.
        • Tajima S.
        • et al.
        Sulfatide elongates dorsal skin flap survival in rats.
        J Surg Res. 2000; 92: 36-41
        • Hardy S.C.
        • Homer-Vanniasinkam S.
        • Gough M.J.
        Effect of free radical scavenging on skeletal muscle blood flow during postischemic reperfusion.
        Br J Surg. 1992; 79: 1289-1292
        • Aladag M.A.
        • Turkoz Y.
        • Sahna E.
        • et al.
        The attenuation of vasospasm by using a SOD mimetic after experimental subarachnoidal haemorrhaga in rats.
        Acta Neurochir. 2003; 145: 673-677
        • Gurlek A.
        • Schusterman M.A.
        • Evans G.R.
        • et al.
        Venous flap ischemia: microcirculatory changes in experimental flaps in a rabbit model.
        J Reconstr Microsurg. 1998; 14: 121-126
        • Im M.J.
        • Manson P.N.
        • Bulkley G.B.
        • et al.
        Effects of superoxide dismutase and allopurinol on the survival of acute island skin flaps.
        Ann Surg. 1985; 201: 357-359
        • Zaccaria A.
        • Weinzweig N.
        • Yoshitake M.
        • et al.
        Vitamin C reduces ischemia-reperfusion injury in a rat epigastric island skin flap model.
        Ann Plast Surg. 1994; 33: 620-623
        • Dolan R.W.
        • Kerr D.
        • Schneiderman T.
        • et al.
        Reducing ischemia-reperfusion injury in rat island groin flaps using dexamethasone.
        Ann Plast Surg. 1995; 35: 285-289
        • Wright J.G.
        • Kerr J.C.
        • Valeri C.R.
        • et al.
        Heparin decreases ischemia-reperfusion injury in isolated canine gracilis model.
        Arch Surg. 1988; 123: 470-472
        • Morris S.F.
        • Pang C.Y.
        • Lofchy N.M.
        • et al.
        Deferoxamine attenuates ischemia-induced reperfusion injury in the skin and muscle of myocutaneous flaps in the pig.
        Plast Reconstr Surg. 1993; 92: 120-132
        • Sud'ina G.F.
        • Mirzoeva O.K.
        • Pushkareva M.A.
        • et al.
        Caffeic acid phenethyl ester as a lipoxygenase inhibitor with antioxidant properties.
        FEBS Lett. 1993; 23: 21-24
        • Bhimani R.S.
        • Troll W.
        • Grunberger D.
        • et al.
        Inhibition of oxidative stress in HeLa cells by chemopreventive agents.
        Cancer Res. 1993; 1: 4528-4533
        • Jaiswal A.K.
        • Venugopal R.
        • Mucha J.
        • et al.
        Caffeic acid phenethyl ester stimulates human antioxidant response element-mediated expression of the NAD(P)H:quinone oxidoreductase (NQO1) gene.
        Cancer Res. 1997; 1: 440-446
        • Chen J.H.
        • Shao Y.
        • Huang M.T.
        • et al.
        Inhibitory effect of caffeic acid phenethyl ester on human leukemia HL-60 cells.
        Cancer Lett. 1996; 108: 211-214
        • Lee Y.J.
        • Liao P.H.
        • Chen W.K.
        • et al.
        Preferential cytotoxicity of caffeic acid phenethyl ester analogues on oral cancer cells.
        Cancer Lett. 2000; 153: 51-56
        • Nardini M.
        • D'Aquino M.
        • Tomassi G.
        • et al.
        Inhibition of human low-density lipoprotein oxidation by caffeic acid and other hydroxycinnamic acid derivatives.
        Free Radic Biol Med. 1995; 19: 541-552
        • Kim S.R.
        • Kim Y.C.
        Neuroprotective phenylpropanoid esters of rhamnose isolated from roots of Scrophularia buergeriana.
        Phytochemistry. 2000; 54: 503-509
        • Koltuksuz U.
        • Ozen S.
        • Uz E.
        • et al.
        Caffeic acid phenethyl ester prevents intestinal reperfusion injury in rats.
        J Pediatr Surg. 1999; 34: 1458-1462
        • Michaluart P.
        • Masferrer J.L.
        • Carothers A.M.
        • et al.
        Inhibitory effects of caffeic acid phenethyl ester on the activity and expression of cyclooxygenase-2 in human oral epithelial cells and in a rat model of inflammation.
        Cancer Res. 1999; 15: 2347-2352
        • Khouri R.K.
        • Angel M.F.
        • Edstrom L.E.
        Standardizing the dorsal rat flap.
        Surg Forum. 1986; 37: 590-594
        • Cetin C.
        • Kose A.A.
        • Aral E.
        • et al.
        Protective effect of fucoidin (a neutrophil rolling inhibitor) on ischemia reperfusion injury: experimental study in rat epigastric island flaps.
        Ann Plast Surg. 2001; 47: 540-546
        • Parlakpinar H.
        • Ozer M.K.
        • Sahna E.
        • et al.
        Amikacin-induced acute renal injury in rats: protective role of melatonin.
        J Pineal Res. 2003; 35: 85-90
        • Cortas N.K.
        • Wakid N.W.
        Determination of inorganic nitrate in serum and urine by a kinetic cadmium-reduction method.
        Clin Chem. 1990; 36: 1440-1443
        • Sahna E.
        • Parlakpinar H.
        • Ozturk F.
        • et al.
        Protective effects of physiological and pharmacological concentrations of melatonin on renal ischemia-reperfusion injury in rats.
        Urol Res. 2003; 31: 188-193
        • Paglia D.E.
        • Valentina W.N.
        Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase.
        J Lab Clin Med. 1967; 70: 158-169
        • Podczasy J.J.
        • Wei R.
        Reduction of iodonitrotetrazolium violet by superoxide radicals.
        Biochem Biophys Res Commun. 1988; 150: 1294-1301
        • Suzuki S.
        • Miyachi Y.
        • Niwa Y.
        • et al.
        Significance of reactive oxygen species in distal flap necrosis and its salvage with liposomal SOD.
        Br J Plast Surg. 1989; 42: 559-564
        • Ames III, A.
        • Wright R.L.
        • Kowada M.
        • et al.
        Cerebral ischemia. II. The no-reflow phenomenon.
        Am J Pathol. 1968; 52: 437-453
        • May J.W.
        • Chait L.A.
        • O'Brien B.M.
        • et al.
        The no-reflow phenomenon in experimental free flaps.
        Plast Reconstr Surg. 1978; 61: 256-267
        • Willemart G.
        • Knight K.R.
        • Morrison W.A.
        Dexamethasone treatment prior to reperfusion improves the survival of skin flaps subjected to secondary venous ischaemia.
        Br J Plast Surg. 1998; 51: 624-628
        • Puckett C.L.
        • Misholy H.
        • Reinisch J.F.
        The effects of streptokinase on ischemic flaps.
        J Hand Surg. 1983; 8A: 101-104
        • Reus W.F.
        • Murphy R.C.
        • Heggers J.P.
        • et al.
        Effect of intraarterial prostacyclin on survival of skin flaps in the pig; biphasic response.
        Ann Plast Surg. 1984; 13: 29-33
        • Tyler H.M.
        • Saxton C.A.
        • Parry M.J.
        Administration to man of UK-37,248-01, a selective inhibitor of thromboxane synthetase.
        Lancet. 1981; 1: 629-632
        • Parry M.J.
        • Randall M.J.
        • Hawkeswood E.
        • et al.
        Enhanced production of prostacyclin in blood after treatment with selective thromboxane synthetase inhibitor UK-38,485.
        Br J Pharmacol. 1982; 77: 547-551
        • Reiter R.J.
        • Tan D.X.
        Melatonin: a novel protective agent against oxidative injury of the ischemic/reperfused heart.
        Cardiovasc Res. 2003; 58: 10-19
        • Birincioglu M.
        • Aksoy T.
        • Olmez E.
        • et al.
        Protective effect of ACE inhibitors on ischemia-reperfusion-induced arrhythmias in rats: is this effect related to the free radical scavenging action of these drugs?.
        Free Radic Res. 1997; 27: 389-396