الفهرس 
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Abstract
The present study is conducted to investigate the effect of XO inhibitors in CYC-induced cardiac and myelotoxicity in rats. Our study is the first that exhibited differential protective and deleterious effects of the XO inhibitor; ALL, in CYC-induced cardiac and myelotoxicity, respectively. In addition, our study also assessed the mechanistic cardiac and myelotoxic protective effect of a relatively novel XO inhibitor; FEB, against CYC-induced toxicity.
In the present work, administration of CYC into rats resulted in cardiotoxicity, manifested by significant changes in the normal level of cardiac enzymes and histopathological disruption. Furthermore, CYC caused changes in the level of oxidative stress parameters (SOD, MDA) in heart tissue. It also caused changes in the activity of cardiac XO enzyme. In bone marrow, CYC treatment caused bone marrow depression as evident by the deterioration of different blood elements and histopathological changes observed in bone marrow tissues obtained from these rats. CYC also altered XO activity in bone marrow.
Over all, the administration of either ALL or FEB improved these abnormalities in the heart of CYC-intoxicated rats. In the bone marrow, on the other hand, FEB improved bone marrow suppression, but ALL did not, compared to CYC-treated group.
In the present study, male albino rats were divided into 6 main groups; control group, ALL-treated, FEB-treated, CYC-treated groups, as well as combination groups of CYC/ALL and CYC/FEB. Administration of ALL and FEB was started at the first day of the experiment, while CYC administration was at the 9th day of the experiment, whereas sacrifice and sample collection was done at day 14 of the experiment.
CYC was administered as a single dose of 200 mg/kg (i.p), and caused a significant increase in serum levels of both LDH and CK-MB as compared with control group. Co-administration of ALL (100 mg/kg/day) with CYC did not affect the serum levels of CK-MB as compared with CYC-intoxicated group. Co-administration of FEB (10 mg/kg/day) with CYC decreased CK-MB level significantly as compared with CYC-intoxicated group. Co-administration of either ALL or FEB with CYC caused significant decrease in serum LDH level as compared with CYC-intoxicated group.
In heart tissue samples from CYC-intoxicated group, the activity of SOD was significantly decreased, while MDA and XO were significantly increased in comparison to control group. Treatment with either ALL or FEB prior to CYC significantly attenuated the effect of CYC on cardiac SOD activity as well as MDA and XO. However, effect on GSH and catalase revealed no changes.
In bone marrow samples, there was no effect of ALL, FEB or even CYC on tissue SOD, catalase or GSH. However, CYC treatment caused increase in MDA level in bone marrow, while co-administration of FEB, but not ALL, restored MDA levels compared to the group treated with CYC alone. As for XO activity, groups treated with ALL, FEB or CYC alone or CYC/FEB, but not CYC/ALL, showed significant increase in XO activity in comparison to control group.
In blood samples from CYC-intoxicated group, haemoglobin level, white blood cell and platelet counts were significantly decreased compared to control. Treatment with ALL did not significantly improve the effect of CYC on blood elements. However, treatment with FEB reversed the effect of CYC on Hb level. The combination of ALL with CYC caused aggravation of RBCs count, which was not seen when each drug was given alone.
Co-treatment with either ALL or FEB improved the microscopic picture in both cardiac and bone marrow tissues in CYC-intoxicated rats, compared to CYC alone.