The protective effect of caffeic acid phenethyl ester against cyclosporine A-induced cardiotoxicity in rats
Introduction
The use of cyclosporine A (CsA) as an immunosuppressant and anti-rejection drug has been related to nephrotoxicity (Rezzani et al., 2002), hypertension (Nishiyama et al., 2003), hepatotoxicity (Durak et al., 2004, Rezzani, 2004) and cardiotoxicity (Bianchi et al., 2003, Rezzani et al., 2003). Studies to elucidate the mechanism(s) of these adverse effects have implicated free radical production (Zachariae, 1999), lipid peroxidation (Wang and Salahudeen, 1995), induction of the cytochrome P450 (CYP450) system (Mayer et al., 1989) and increased synthesis of vasoconstrictor eicosanoids, mainly tromboxane A2 (TxA2) (Perico et al., 1986, Bianchi et al., 2003). CsA is also an inducer of the powerful vasoconstrictor endothelin (ET), whose levels are elevated after CsA treatment in experimental and clinical conditions (Rezzani et al., 2001, Cauduro et al., 2004). Although mechanisms by which CsA induced toxicity are still not clear and still matter of debate, several reports have suggested that oxidative stress is a possible pathway of CsA toxicity (Grieve and Shah, 2003, Rezzani et al., 2003). Oxidative stress is defined as a tissue injury referring to an imbalance between the production of reactive oxygen species (ROS) and endogenous antioxidant defence systems. Under these conditions, the endogenous antioxidants such as catalase, superoxide dismutase, glutathione and cytochrome-c-oxidase, may be unable to counter ROS formation. So, their presence may cause cellular damage by peroxidation of membrane lipids, sulphydryl enzyme inactivation, protein crosslinking and DNA breakdown (Ilhan et al., 2004). Moreover, it is known that, in heart failure, the ROS production activates latent resident matrix metalloproteinase (MMP) enzymes (Siwik and Colucci, 2004) and induces a decrease in their endogenous inhibitors (TIMPs). The MMPs are a family of enzymes capable of matrix component degradation and they are critically important in determining the balance between matrix deposition and degradation, which ultimately influences chamber size, shape and function (Grieve and Shah, 2003). So, the inappropriate activation of MMPs and/or an imbalance between their actions and those of their inhibitors, for example due to ROS increase, are implicated in cardiac remodelling (Spinale, 2002). According to these data, in our previous works, we observed, after experimental CsA treatment, an increase in MMP2 activity and myocardial extracellular matrix (ECM) disorganization with the disappearance of normal network among the fibers (Bianchi et al., 2003). Moreover, other authors, evaluating the dysregulation of the myocardial ECM in different cardiomyopathies, demonstrated an evident MMP2 upregulation with an inhibition of endogenous antioxidant systems (Siwik et al., 2001). So, more attention have been paid to the protective effects of natural antioxidants against drug-induced toxicities (i.e. CsA) especially whenever free radical generations are involved. Caffeic acid phenethyl ester (CAPE), a flavonoid-like compound, is one of the major components of honeybee propolis with several biological and pharmacological properties. It has been demonstrated that CAPE has antioxidant (Ramazan Yilmaz et al., 2004), anti-inflammatory (Michaluart et al., 1999), anti-carcinogenic (Chen et al., 2001), antiviral (Fesen et al., 1994) and immunomodulatory activities (Park and Kang, 1999). Moreover, it prevents lipid peroxidation induced by ischaemia-reperfusion injury in renal tissue, spinal cord and brain (Irmak et al., 2001, Irmak et al., 2003). At a concentration of 15 μmol/kg/day CAPE completely blocks the production of ROS in human neutrophilis and the xanthine/xanthine oxidase system (Sud’ina et al., 1993). Moreover, it inhibits inducible nitric oxide synthase by increasing leukocyte apoptosis and decreasing leukocyte concentration (Song et al., 2002).
The hypothesis tested is that CAPE is able to reduce or block CsA cardiotoxicity by its antioxidant properties. We have also examined, by morphological and biochemical studies, whether side CsA effects might be related to: (1) an imbalance between the activities of MMP2 and its inhibitor, TIMP2; (2) a decrease in antioxidant markers such as cytochrome-c-oxidase.
Section snippets
Drugs
CsA (Sandimmun, Sandoz) and CAPE (Sigma–Aldrich, Italy) were both dissolved in olive oil. Their final concentration was of 15 mg/kg for CsA and 15 μmol/kg for CAPE during the experimental treatment. They were subcutaneously injected daily during all treatment. The CsA and CAPE doses have been chosen, respectively, according to Schuurman et al. (1990) and Doganay et al. (2002).
Animals and experimental groups
This study included 64 adult male Wistar rats weighing 200–250 g. The animals were housed in cages and kept on a 12 h
Results
The morphological and biochemical results were similar in control and CAPE alone treated rats, so we decided to consider them without distinction.
Discussion
In this study, we showed, first, that CsA determined: (1) upregulation of MMP2 and downregulation of TIMP2 mediated by ROS production; (2) decrease in cytochrome-c-oxidase expression and increase in ROS production. In particular, the increase in MMP2 and decrease in TIMP2 expression should be a compensatory mechanism against the excessive accumulation of collagen. However, in this and in our previous work (Bianchi et al., 2003) we observed that this alteration in MMP2 and TIMP2 proteins is not
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