الفهرس 
1.Introduction and Aim of the Work
3.Mechanisms of DOX-Induced CardiomyopathyOnly 14 pages are availabe for public view
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Abstract
Doxorubicin or Adriamycin® or Doxil® is most commonly used an effective chemotherapeutic drug for the treatment of a wide range of cancers including both the solid and hematogenous cancers. However, its clinical use is limited by its side effects on several organs especially the heart and liver. chronic administration of doxorubicin is associated with the development of cardiomyopathy which eventually leads to fatal congestive heart failure and hepatotoxicity . Free radical generation plays the major role in Dox-induced cardiotoxicity. Elevated free radical generation may cause a variety of subcellular changes in the myocardium, including the slow loss of myofibrils and vacuolization of myocardial cells. In addition, DOX administration is associated with a decrease the endogenous antioxidants responsible for the scavenging of free radicals. Therefore uptake of components as free radical scavengers may contribute to the enhancement of antioxidant defense system, providing protection to a greater extent. The aim of this study is to evaluate the cardioprotective and hepatoprotective effects of TRE on DOX-induced cardiomyopathy in mice. Female BALB/c mice, (n=60) weighing 20-25 g were divided into five groups, each group included 12 mice, as following: group I: (Negative control group); Mice were injected with normal saline(0.9% w/v, 200μl/mouse) intraperitoneally (i.p.) per time, nine times day other day. group II:(Doxorubicin group); Mice were injected with 2 mg doxorubicin/kg body weight per time , three times per week for three weeks day other day . GroupIII:(Trehalose control group); mice were injected with trehalose(200 μg/mouse dissolve in normal saline(0.9%w/v),200 μl/mouse(i.p) per time , nine times day other day . GroupIV:(Doxorubicin + trehaalose at same time co-treatment group); mice were injected with 2 mg doxorubicin/kg body weight as GP II ,and at same time were injected with TRE (200 μg/mouse as GPIII. Chapter6 Summary and conclusion 108 GroupV:(Doxorubicin +then 18 days injected with trehalose posttreatment group); mice were injected with 2 mg doxorubicin/kg body weight as Gp II , then 18 days mice were injected with TRE (200 μg/mouse as Gp III . At the end of the experiment(57 days) mice were euthanized . Specimens Blood Specimens A-Blood Sampling Blood samples were collected into tubes and allowed to clot at room temperature. There after; serum was separated by centrifugation at 3000 rpm for 15 minutes and kept at -20 oC until assay. Serum of all forementioned groups was subjected to the following determinations: • Lactate dehydrogenase (LDH) and CK-MB (creatine kinasemuscle/ brain),activities. • Glutamate-pyruvate transaminase (SGPT) and Aspartate Aminotransferase (AST) activities. • Troponin I activity 3.6.3. Tissue samples Hearts and livers were removed, cleaned, washed in ice-cold physiological saline and divided into two parts; one of them was fixed in formalin for histopathological examination, the other part was homogenized (10% w/v) in 0.05M phosphate buffer then centrifuged at 3000 rpm for 15 min. The supernatant was used for determination of the following: Heart tissues: • Total antioxidant capacity(TAC)level. • Catalase (CAT) enzyme activity. • Glutathione S-transferases (GSTs) activity. • Malondialdehyde (MDA) level. • Myeloperoxidase (MPO) activity. • Autophagy related 5(ATG5) level. Liver tissues: • Total antioxidant capacity(TAC)level. • Catalase (CAT) enzyme activity. • Total thiol level. • Malondialdehyde (MDA) level. Results were statistically analyzed and can be summarized as the following Body weight and heart weight of mice treated with DOX (GP II) significant decreased compared to other group. On other hand mice treated with TRE(GP III) significant increase in body weight compared to DOX group. However, RHW of mice treated with DOX group significant increase compared to all group. Liver weight and RLV of mice treated with DOX (GP II) significant decreased compared to other group. On other hand mice treated with TRE (GP III) significant increase in liver weight compared to DOX group. Serum ALT and AST activities were significant increase in mice treated with DOX compared to all group. However, mice administration with TRE co-treatment with DOX at same time significant decreased compared to DOX. Serum LDH , CK-MB,cTnI activities were significant increase in mice treated with DOX compared to all group. However, mice administration with TRE co-treatment with DOX at same time(GP IV) and post-treatment(GP V) were significant decreased compared to DOX group. Heart glutathione S-transferase (GST) activity of DOX group was significant decreased compared to all group. However ,TRE in cotreatment and post-treatment plus DOX were significant decreased compared to TRE group(GP III). While, Heart myeloperoxidase (MPO) activity of DOX increased significant compared to all group. However, mice administration with TRE plus DOX in co-treatment group (GP IV) and in post-treatment GP V was significant increased compared to GP I (saline) and GP III(TRE). Also , Heart catalase activity of DOX decreased significant compared to all groups. Malondialdehyde (MDA) level in heart was significant increased in mice treated with DOX group compared to all group. However , mice administration with TRE plus DOX in co-treatment group (GP IV) was significant decreased compared to GP I (saline). Also, heart total antioxidants capacity (TAC) level of mice treated with DOX were significant decreased compared to all groups. On other hand , Hepatic catalase activity was significant decreased in mice treated with DOX group compared to all group. ,while mice administration with TRE (GP III) ,TRE plus DOX in co-treatment group (GP IV)and TRE plus DOX in post-treatment group (GP V) were significant increased in mice treated with DOX group (Gp II) and saline group (GP I). However, Malondialdehyde (MDA) level in liver was significant increased in mice treated with DOX group compared to all group. However , mice administration with TRE plus DOX in co-treatment group (GP IV) and post-treatment group (GP V) were significant increased compared to GP I (saline)and GP III (TRE). Also, Liver total antioxidants capacity (TAC) level of mice treated with DOX were significant decreased compared to all groups. While , Total thiol level in liver of mice treated with DOX was significant decreased compared to all groups. However , mice administration with TRE plus DOX in co-treatment group (GP IV) and post-treatment group (GP V) were significant decreased compared to GP III (TRE). Also, heart ATG5 level of mice treated with DOX group in was significant increased in compared to all group. However , mice administration with TRE plus DOX in co-treatment group (GP IV) and post-treatment group (GP V) were significant increased compared to GP III (TRE). The histopathology of heart from mice that injected with DOX showed focal hyalinization in myocardium with few inflammatory cells infilteration in subendocardium compared to control group. On other hand, The histopathology of heart from mice that administration with TRE plus DOX in co-treatment (GP IV) and post-treatment showed normal histological structure of myocardium compared to mice treated with DOX only. The histopathology of liver from mice that injected with DOX showed dilceration and congestion of portal vein with massive aggregation of inflammatory cells surrounding the bile duct in portal area as well as degeneration of the hepatocytes in the parenchyma compared to control group. on other hand The histopathology of liver from mice that administration with TRE plus DOX in co-treatment (GP IV) and posttreatment showed significant improvement in hepatic parenchyma compared to mice treated with DOX only.