Abstract
Doxorubicin (DOX) is a powerful anticancer agent with sever cardiotoxic side effect which limits the clinical use. Metformin (MET) is antihyperglycemic drug with potential cardioprotective effect via AMP-activated protein kinase (AMPK) (increases fatty acid oxidation, decreases the production of ROS, maintaining energy homeostasis and apoptosis). Metabolomics technology deals with systematic study of chemical fingerprints of metabolite profiles. Different metabolic processes can be identified which will give information of any change in the metabolic profile of tissues as well as of biofluids after drug administration. This research designed to investigate MET cardioprotective effect against acute cardiotoxicity induced by DOX using metabolomics technology. Methods: Twenty four adult male wistar rats divided into four groups (6 animals each): control group (saline, i.p.); MET group (300mg/kg/day for 7dayes) by gavage; DOX group (20 mg/kg,i.p.) for acute induction of cardiotoxicity; Met + DOX group received DOX (20mg/kg i.p.) and Met (300 mg/kg/day, for 7 days, starting five days prior to DOX treatment) orally with gavage. Assessment of heart tissue metabolomics, serum MDA and GSH in addition to trichrome stain. Results: The results showed that pretreatment with MET (MET+DOX) significantly (p<0.05) reduced the level of acetic acid, cholesterol, palmitic acid, phosphoric acid, pyruvic acid, stearic acid, glucose, myo-inositol, alanine, lysine, and proline. Also, the level of arachidonic acid, hydroxybutyric acid, lactic acid, linoleic acid, oleic acid, oxalic acid, propionic acid, and galactose reduced after pretreatment with MET (MET+DOX). Additionally, (MET +DOX) resulted in significant decrease (p<0.05) in the level of serum MDA as well as significant (p<0.05) increase in serum GSH levels. In addition to significantly decreased collagen fiber production. Conclusion: It can be concluded that MET improved cardiac structure and function, as well as the metabolism of DOX-induced cardiotoxicity group, as it reduced the level of biomarkers associated with cardiotoxicity including (arachidonic, linoleic, oleic, acetic, stearic) acids, cholesterol ,leucine, glucose, mannose, myoinositol as well as hydroxybutyric acid. This indicates that MET induced a metabolic alterations, including the promotion of glycogenolysis, glycolysis, amino acid utilization and antioxidation. Additionally, MET improving energy metabolism and attenuating oxidative stress through suppression of serum MDA and increase the level of GSH as well as decrease fibrosis and structural changes.

Key words: metabolomics, cardiotoxicity, doxorubicin, cardioprotection, metformin.