Protective effect of N-acetylcysteine on cyclophosphamide-induced cardiotoxicity in rats
Graphical abstract
Introduction
Cyclophosphamide (CP) is an alkylating agent widely used for the treatment of chronic and acute leukemias, lymphoma, multiple myeloma, neuroblastoma, retinoblastoma, and cancers of the breast and ovary. It is also used to treat some non-cancerous conditions (Al-Yahya et al., 2009). CP used in regimen prior to stem cell transplantation and in low doses in the treatment of several autoimmune diseases (Luznik and Fuchs, 2010). CP is metabolized by hepatic cytochrome P450 to form 4-hydroxycyclophosphamide that produces the chemically reactive metabolites phosphoramide mustard and acrolein that alkylate DNA and protein, producing cross-links (Georgia et al., 2005). It has been shown that CP treatment induces hemorrhagic cystitis, hepatic and lung damage as well as cardiotoxicity and nephrotoxicity (Cho et al., 2010, Oter et al., 2004, Singh et al., 2014).
During activation of CP by cytochrome P450, generation of reactive oxygen species (ROS) such as superoxide anions was demonstrated (Stankiewicz and Skrzydlewska, 2005). CP metabolites, and ROS generated in particular, can cause changes in cell redox balance, which leads to oxidative stress, resulting in cancer and healthy cell damage (Abraham et al., 2011; Jamshidzadeh et al., 2009). Moreover, superoxide radical may react with other radicals including nitric oxide producing peroxynitrite, in the cytosol and mitochondria (Mukhopadhyay et al., 2009). In the mitochondria, peroxynitrite may impair various key mitochondrial enzymes leading to more sustained intracellular ROS generation, resulting in an augmentation of oxidative/nitrosative stress. Peroxynitrite also causes strand breaks in DNA and activating the nuclear enzyme poly (ADP-ribose) polymerase-1 (PARP-1). Overactivated PARP initiates an energy-consuming cycle by transferring ADP-ribose units from NAD+ to nuclear proteins, resulting in the rapid depletion of intracellular NAD+ and ATP pools, slowing the rate of glycolysis and mitochondrial respiration, eventually leading to cellular dysfunction and death, commonly by necrosis (Pacher et al., 2007). Overactivated PARP may also facilitate the expression of a variety of inflammatory genes leading to increased inflammation and associated oxidative stress (Pacher and Szabó, 2008), thus facilitating the progression of cardiovascular dysfunction and heart failure. At the advanced stage of severe cardiac dysfunction/heart failure, secondary pathways may also be activated [e.g., proinflammatory cytokines (TNF-α and IL-6)] acting directly on the myocardium or indirectly via changes in hemodynamic loading conditions causing additional oxidative/nitrosative stress, endothelial and myocardial dysfunction, cardiac and vascular remodeling with hypertrophy, fibrosis, cardiac dilation, and myocardial necrosis, leading eventually to heart failure (Pacher et al., 2007).
N-acetylcysteine (NAC) is an antioxidant with free radical scavenging activity that restores the pool of intracellular reduced glutathione (GSH), which is often depleted as a result of increased status of oxidative stress and inflammation (Goncalves et al., 2010). NAC acts as a precursor for GSH biosynthesis as well as a stimulator of the cytosolic enzymes involved in glutathione regeneration (Shivalingappa et al., 2012). NAC has a protective effect against isoproterenol-induced cardiotoxicity (Nagoor Meeran and Mainzen Prince, 2011) and doxorubicin-induced cardiac damage (Arica et al., 2013). NAC have been found to have diverse therapeutic actions including vasodilation effect due to an increase in cyclic guanosine monophosphate levels, platelet aggregation inhibition, sulphydryl group donation to regenerate endothelial-derived relaxing factor and reduces in IL-8 and TNF-α production (Kekec et al., 2010).
N-acetylcysteine has a variety of mechanisms and protective effects towards DNA damage and carcinogenesis, which are related to its nucleophilicity, antioxidant activity, modulation of metabolism, effects in mitochondria, modulation of DNA repair, regulation of cell survival and apoptosis (Mansour et al., 2008).
This study is designed to study the effects of N-acetylcysteine (NAC) on cyclophosphamide-induced cardiac toxicity in rats.
Section snippets
Drug and chemicals
Cyclophosphamide and N-acetylcysteine acid were purchased from Sigma Chemical Co., St. Louis, MO, USA. They were dissolved in normal saline solution immediately before injection to the animals in order to attain the required dose. All the other chemicals used were of the highest analytical grade.
Animals
Experimental animals male albino rats of Wistar strain weighing 150–170 g used in the present studies were procured from the animal house of the National Cancer Institute, Cairo, Egypt. All the animals
Results
Rats treated with CP showed a significant increase (p < 0.05) in the serum activities of ALT, AST, CK and LDH compared to the normal control rats. Treatment with NAC (200 mg/kg) daily for 5 days prior to CP significantly decreased (p < 0.05) the serum activities of ALT, AST, CK and LDH compared with CP treated rats (Table 1).
The level of TNF-α was significantly enhanced (p < 0.05) after CP-administration compared to the normal control group. Treatment of rats with NAC prior to CP induced a significant
Discussion
In the present study, CP administration significantly increased the activities of serum ALT, AST, CK and LDH. These observations are consistent with previous studies (Asiri, 2010, Nagi et al., 2011). CP is a cardiotoxic agent inducing a direct myocardial endothelial damage and destruction of myocardial cells. As a result, ALT, AST, CK, and LDH are released into the blood stream and serve as the diagnostic markers of myocardial tissue injury (Viswanatha et al., 2013). Elevated levels of serum
Conclusion
The results from the present investigation indicate that NAC pretreatment protects against CP-induced cardiotoxicity by decreasing oxidative and nitrosative stress and preserve the activity of antioxidant enzymes.
Conflict of interest statement
The author reports no conflicts of interest. The author alone is responsible for the content and writing of the paper. No source of fund.
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