Doxorubicin an anthracycline antibiotic widely used broad spectrum chemotherapeutic agent against various malignancies such as leukemias, lymphomas and several solid tumors. However, its clinical use is restricted because of its serious dose dependent cardiotoxicity. Clinical and experimental investigations recommended that increased oxidative stress plays a critical role in subsequent cardiomyopathy and heart failure associated with doxorubicin treatment (Singal, P.K and Iliskovic, N., 1998). The mechanism by which DOX causes myocardial injury is not clearly understood. However, Rahila Ahmed et al., 2010 reported that doxorubicin is converted into its semiquinone form in the cardiac myocytes by mitochondrial CYP450 and flavin monoxygenases, which is a toxic and short lived metabolite, interacts with molecular oxygen, initiates a cascade of reactions, and produces reactive oxygen species (ROS). The present study is aimed to explore the cardioprotective effect of oral administration of bark extract of Terminalia paniculata against doxorubicin induced cardiotoxicity in rats.
Doxorubicin induced mortality showed excessive degree of pericardial, pleural and peritoneal effusion (Hayward R et al., 2007). Ascites has been reported to be a characteristic of DOX-induced heart failure. Some researchers have dismissed the accumulation of ascetic fluid as evidence of DOX-mediated heart failure, whereas others have assessed the degree of heart failure according to the volume of the ascetic fluid (Andrew and Arthur, 2006). In the present study, animals administered with doxorubicin accompanied by the high mortality rate compared to control group. The ability of EETP to protect against DOX-induced high mortality was considered an early sign of cardioprotection.
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Doxorubicin induced cardiotoxicity is characterized by increased in the heart weight. The results of the present study confirmed the earlier findings that animals treated with doxorubicin caused a significant increased in the heart weight. The observation that EETP and Vit E treatment showed lesser increment in the heart weight when compared to ischemic control animals.
The serum enzymes viz AST and ALT serve as sensitive indices to assess the severity of myocardial infarction (P.Muralidharan et al, 2008). When myocardial cells containing AST and ALT, are damaged or destroyed due to deficient oxygen supply, the cell membrane become permeable or may rupture (Senthil.S et al., 2007). Due to impaired cellular integrity of myocardium, these marker enzymes get leaked in the blood stream. In the present study, near normal activity of the diagnostic marker enzymes in the serum of rats treated with EETP and Vit E challenged with doxorubicin is an indicative of the fact that EETP has significant cardioprotective effect.
CKMB and LDH, cardiac enzymes found primarily in the myocardium are used to evaluate the existence and extent of myocytes injury (Gurvinder Singh et al., 2008). The increase of these biomarkers in serum and extracellular fluid suggests an increased leakage of these enzymes from mitochondria as a result of toxicity induced by the treatment with doxorubicin. It is widely reported that doxorubicin induced free radical generation triggers membrane peroxidation and disruption of cardiac myocytes, which can lead to increased release of CK-MB and LDH in the serum (Herman, E et al., 1971). We have shown that EETP pretreatment lead to inhibition of CKMB release in a dose-dependent manner. There was a near complete inhibition of CKMB & LDH release in Dox-treated animals at the highest concentration of EETP evaluated by us. Vit E administered group showed the equipotent cardioprotective effect as EETP.
Troponins are regulatory proteins essential for contraction and relaxation processes in myocardium. Increase in Troponin I level indicate damage to the contractile protein which is responsible for the release of structurally bound troponin I used as a marker for the detection of cardiac injury in laboratory animals (J.P Bertinchant et al., 2003). Eugene H., et al 1998 reported that cTnT and cTnI was a useful marker for the prediction of experimentally induced anthracycline cardiomyopathy and for the evaluation of cardiotoxic and possibly cardioprotective effects of a new drug. In the present study, administration of EETP prevented the doxorubicinââ‚¬"induced release of troponin I from myocardium into the blood stream, there by demonstrating its protective action on the cell membrane. Vit E administration showed no significant cardioprotective activity compare to EETP against negative control. This perhaps is possible through the maintenance of the delicate balance of tonicity in cells in the myocardium.
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Hanan H, 2002 showed that mild hyperhomocysteinemia is associated with an increased risk of cardiovascular diseases independently of classical risk factors. Elevated level of homocysteine has been reported to be associated with increased interleukin production in monocytes and up regulation of vascular cell adhesion molecules (Stampfer M.J et al 1992). In the present study a significant increase in the level of homocysteine in serum of Doxorubicin control rats was observed. Oral pre treatment with EETP and Vit E significantly reduced the level of homocysteine in serum; this might be attributed to the inhibition of the production of monocyte/macrophage derived interleukins.
There is evidence that high serum uric acid is a negative prognostic factor for mortality in subjects with pre-existing heart failure or coronary artery disease and cardiovascular events (Nadkar MY et al., 2008). One mg/dl increase in serum uric acid levels was associated with 26% increase in mortality. In the present study, doxorubicin administered group showed a significant increase in serum uric acid levels. EETP pre-treated group showed reduced level of uric acid. However there is less significant reduction in animals treated with Vit E.
Recent studies indicate that accelerated degradation of membrane phospholipids is very likely the biochemical basis for the irreversible cell injury and myocardial ischaemia (Narshimhan LP., et al 1990). Activation of lipid peroxidation corresponded with the changes in lipid composition. Alteration in lipid composition observed in necrosis impaired myocardial tissue appears to occur due to destruction of cardiomyocytes (A. Paritha et al., 1997). In doxorubicin administered rats, cholesterol and triglycerides in LDL and VLDL fractions increased significantly with a significant decrease in HDL cholesterol. In rats treated with EETP and Vit E + doxorubicin the levels of cholesterol and triglycerides in the lipoprotein fractions were retained at near normal values. HDL is known to be involved in the transport of cholesterol from the tissues to the liver for catabolism. Increase in the myocardial cholesterol on doxorubicin administration could be due to increased direct uptake of LDL from the blood by the tissues. The abnormal cholesterol deposition is favored by the dangerous tendency of cholesterol to passive exchange between the plasma lipoproteins and cell membranes (Ram A et al., 1997). The high level of VLDL, triglycerides on doxorubicin administration could be due to the decreased activity of extra hepatic lipoprotein lipase (Herman, E., et al 1971). Thus this study reveals some significant alterations in serum HDL-cholesterol, triglycerides, total cholesterol, LDL and VLDL-cholesterol after acute episode of myocardial infarction.
The presented experimental evidence suggests that Dox induced oxidative stress is due to the generation of free radicals in the heart tissue (Shoko Ichihara et al., 2007). The principle ROS generated are hydroxyl radicals and superoxide radicals, which have the potential to cause damage to various intracellular components (B.C.Koti et al, 2008). Cardiac muscle is particularly susceptible to free-radical injury, because it contains low levels of free-radical detoxifying enzymes/molecules like superoxide dismutase, catalase and GSH. Furthermore, Dox also has high affinity for the phospholipids component of mitochondrial membrane in cardiac myocytes, leading to accumulation of Dox in the heart tissue (Takacs et al., 1992).
Further, a significant increase in the levels of lipid peroxides in serum was observed in the rats treated with doxorubicin, which is known to produce experimental myocardial infarction. Lipid peroxidation is responsible for cellular damage and is primarily known to cause ROS-induced organ damage (B.C.Koti et al., 2007). Depletion of glutathione is known to result in enhanced LPO and excessive LPO can cause increased glutathione consumption (Ipseeta M et al., 2004) as observed in the present study. Our studies have shown that Dox-induced considerable increase in lipid peroxidation, which was significantly prevented by EETP and Vit E pretreatment.
The activity of SOD, CAT, GSH, GPx and GR was significantly decreased in Dox-treated animals and the pretreatment with EETP and Vit E reversed their activity and showed a significant raise in their levels. However, it has been reported that an increase in SOD activity, without a concomitant rise in the activity of catalase/GSH might be unfavorable (Naidu et al., 2002). This is due to the fact that SOD gives rise to hydrogen peroxide as a metabolite, which is cytotoxic and needs to be scavenged by catalase/GSH. Thus a simultaneous raise in catalase/GSH activity is essential for an overall beneficial effect of increase in SOD activity (Huda Alkreathy a.,et al,2010). Inhibition of Dox-induced oxidative stress and tissue injury might be due to an increase in GSH, myocardial SOD and catalase activities, following the administration of experimental drugs.
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ROS impairs the function of isolated mitochondria and subsequently result in adenosine (ATP) depletion. Like Ischemia and repefusion, exposure of isolated sarcoplasmic reticulum to ROS results in a diminished calcium uptake and depresses Ca2+ATPase and Mg2+-ATPase activity. Likewise, ROS have been shown to reduce calcium stimulated ATPase activity and slow down calcium transport in the sarcolemma. Hence, the disturbances in calcium homeostasis occurs due to the ROS interactions with cellular membranes could explain some of the contractile abnormalities associated with I/R (Simpson PJ and Lucchesi BR., 1987). ATPases pay significant role in the contraction and relaxation cycles of the cardiac muscle by maintaining normal ion levels within the myocytes. Several factors are known to modify the levels of ATPase, especially lipid peroxidation and membrane fluidity. It has been reported that doxorubicin treatment resulted in a decrease in the activities of membrane-bound ATPases resulting in the enhanced calcium influx into ventricular cell through stimulation of the voltage dependent calcium sodium slow channels; which in turn result in the intracellular accumulation of calcium ions (Renee C, et al., 1983). The results obtained in this study also correlates with the previous reports.
The failure in ATPase activity in the ischemic condition may be responsible for causing not only functional damage but also irreversible necrotic changes in the involved myocardial cell. Peroxidation of membrane lipids could inactivate Na+K+ ATPase and Ca2+ATPase because of the oxidation of ââ‚¬ËœSHââ‚¬â„¢ groups present in its active site resulting in the conformational changes in the enzymes (Kako et al., 1988). Decrease in the activity of Ca2+ATPase can increase intracellular concentration of free Ca2+ and alter the signal transduction pathways and cellular fluidity (Levy et al., 1986). The present study shows that the altered activity of the membrane-bound ATPases by doxorubicin was protected by pretreatment with EETP and Vitamin E. This could be due to the anti-oxidative effect of experimental drugs against ROS induced by doxorubicin. Thus the above observations suggest that the bark extract of Terminalia paniculata possess inotropic activity.
Myocardial damage is specific to all anthracycline antibiotics, exhibited myocardial lesions mainly cytoplasmic vacuolization, myofibrillar loss, swelling of mitochondria, mitochondrial degeneration, formation of lysosomal bodies and dilation of sarcotubular system (Danesi et al., 1992). In the present study electron microscopic evaluation of the rat myocardium revealed that Dox caused mitochondrial swelling, myofibrillar loss, focal dilatation of SER and lipid inclusions. Similar alterations in Dox-treated animals have been reported earlier also (P. DziËâ€ºegiel et al, 2002). The chronic pretreatment of Wistar rats with EETP and Vitamin E was able to protect the rat heart from Dox-induced myocardial injury with significant reduction in the intensity and extent of toxic changes.