Abstract
Cyclosporine-A (CsA) has a potent immunosuppressive activity and is commonly used as anti-rejection drug after organ transplantation and for treatment of some autoimmune diseases. Several toxic effects on the cardiovascular system have been reported with CsA therapy. The toxicity induced by CsA is attributed to the formation of free oxygen radicals. Coenzyme Q10 (CoQ10) is a fat soluble, vitamin-like benzoquinone compound that functions primarily as an antioxidant, and a cofactor in the oxidative phosphorylation processes. The level of CoQ10 is reduced under the conditions of illness for example after renal transplantation. The present study was done aiming to detect the possible morphological and structural changes that may occur in the cardiac muscle of the adult male albino rats duo to CsA therapy and to test the protective effect of CoQ10 against CsA-induced cardiotoxicity. Thirty adult male albino rats were used in this study. They were classified into 3 groups and orally given the following materials for 28 days: Group (1) (Control group): that was further subdivided into 2 equal subgroups, each of 5 animals: subgroup 1a: received olive oil 1 ml/kg. Subgroup 1b: (CoQ10 group): received 5 mg/kg/day of CoQ10. Group (2) (CsA-treated group): The rats received 25 mg/kg/day of CsA. Group (3)(CoQ10 & CsA treated group): The rats were treated with the previously mentioned doses of both CoQ10 and CsA. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were recorded three times per week. At the time of sacrifice, the hearts were dissected out and processed for light and electron microscopic examination. Oral administration of CsA, produced a significant (p<0.05) elevation in SBP, DBP, and HR in comparison to the control group. Treatment with CoQ10 significantly (p<0.05) reduced the increments in arterial blood pressure and heart rate. However, the recorded values were still significantly (p<0.05) higher than that of the control group. The light microscopic study of sections of cardiac muscle of CsA-treated adult male albino rats showed increase in the number of infiltrated cells and disorganization of myocardial fibers with increase in the amount of connective tissue and interstitial fibrosis with perinuclear cytoplasmic vacuolation and decrease in the amount of myofilaments. Electron microscopy showed distension of the Z lines with disintegration of some of them, loss of some microfilaments and disorganized intercalated discs. CoQ10 partially prevented most of the pathological changes revealed by the light and electron microscope. From the above mentioned results we could conclude that treatment with CoQ10 partially prevented the CsA-induced cardiotoxicity in adult male albino rats. We could recommend using CoQ10 during CsA therapy to prevent its cardiotoxicity.
Highlights
Cyclosporine A (CsA), a natural polypeptide with potent immunosuppressive activity, was derived from extracts of Topocladium inflatum gams, a member of the Fungi imperfecti family (Kahan, 1999)
Mechanisms by which CsA-induced toxicity are still not clear, the former clinical and experimental findings have suggested that formation of free oxygen radicals, lipid peroxidation, and induction of cytochrome P-450 system and oxidative stress is a possible pathway of CsA-induced toxicity (Sanchez et al, 2001 and Bianchi et al, 2003)
Interstitial cellular infiltration was recognized (Fig.2). These changes were associated with presence of extravasated red blood cells among muscle cells as well as wide interstitial spaces were revealed (Fig.3) Co-administration of Coenzyme Q10 (CoQ10) and CsA showed that most of the muscle fibers exhibited nearly normal appearance
Summary
Cyclosporine A (CsA), a natural polypeptide with potent immunosuppressive activity, was derived from extracts of Topocladium inflatum gams, a member of the Fungi imperfecti family (Kahan, 1999). CsA is commonly used as anti-rejection drug for organ transplantation and for treatment of some autoimmune diseases (Ponticelli, 2005). Mechanisms by which CsA-induced toxicity are still not clear, the former clinical and experimental findings have suggested that formation of free oxygen radicals, lipid peroxidation, and induction of cytochrome P-450 system and oxidative stress is a possible pathway of CsA-induced toxicity (Sanchez et al, 2001 and Bianchi et al, 2003). Oxidative stress is defined as a tissue injury due to imbalance between the production of oxidants and endogenous antioxidant defense systems of an organism. On the other hand super oxide dismutase, catalase, glutathione peroxidase and cytochrome-c oxidase are endogenous antioxidants which play a role in the prevention of oxidative injury (Akyol et al, 2002)
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