Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

Background:Doxorubicin (DOX), an anthracycline antibiotic, is an important antineoplastic agent due to its high antitumor efficacy in haematological, as well as in solid malignancies. The clinical use of DOX is limited due to its cardiorenaltoxic side effects. Aim: The present study aimed to investigate the possible protective effect of olmesartan (Olm) or L-carnitine (L-CA) and their combination in cardiorenaltoxicity induced by Doxorubicin (DOX) in rats. Methods: Male albino rats were randomly divided into seven experimental groups (n=8): Group I: normal control, group II: L-CA, Group III: Olm, Group IV: DOX.The other three groups were treated with Olm, L-CA and their combination for 2 weeks, after induction of cardiorenaltoxicityby a single dose of DOX. On the last day of treatment, rats were anaesthetized with thiopental, then their echocardiograph (echo-c) was recorded and blood samples were collected to determine troponin I, creatine kinase-MB (CK-MB), lactate dehyclrogenase (LDH), creatinine (Cr), blood urea nitrogen (BUN) and kidney injury molecule-1 (KIM-1)in order to assess cardiac and renal functions. Furthermore, rats were sacrificed by cervical dislocation, and the heart and kidney were excised and homogenized to assess oxidative stress markers such as, reduced glutathione (GSH), malondialdehyde (MDA), and superoxide dismutase (SOD) in both tissues.The proposed possible anti-inflammatory effects were investigated through determination of tumor necrosis factor-alpha (TNF-Ü), intercellular adhesion molecules-1(ICAM-1), interleukin IL-1Ý (IL-1 Ý), myeloperoxidase (MPO), nuclear factor- kappa B (NF-kB) and transforming growth factor Beta (TGF-Ý), which has emerged as having a key role in the development of cardiorenal hypertrophy.Furthermore, Immunohistochemical staining of caspase-3 in both heart and kidney tissues was performed, as key marker of apoptosis. Finally, histopathologicalexaminationsof both heart and renal tissues wereperformed. Results:DOXshowed a significant elevation in serum troponin I, CK-MB, LDH and creatinine, BUN as well as KIM-1. Moreover, DOXshowed a significant increase in TNF-Ü, ICAM-1, IL-1, MPO, NF-kB and TGF-Ýin both cardiac and renal tissues. While, DOX showed a significant increase in MDA and decrease in SOD and GSH in both heart and renal tissuesOn the other hand, administration of L-CA and Olm attenuated DOX-evoked disturbances in the above mentioned parameters

Issued also as CD