Sys Rev Pharm 2021;12(3):100-109 A multifaceted revieMw jouernatl ian thbe fioeld lofophamrmaciycs Of Metformin's Cardioprotective Effect In Acute Doxorubicin Induced- Cardiotoxicity In Rats Lubna Zuhair Abdul Karim *, Inam Sameh Arif **, Fouad A. Al Saady *** *Pharmacist, Department of Pharmacology and Toxicology, College of Pharmacy, Mustansiriyah University, M.Sc. program, Iraq. **Assist.Prof., Department of Pharmacology and Toxicology, College of Pharmacy, Mustansiriyah University, Iraq. *** Assist. Prof., Department of pharmaceutical chemistry, College of Pharmacy, Mustansiriyah University, Iraq. Corresponding author: Lubna Zuhair Abdul Karim *e-mail: [email protected] ABSTRACT Doxorubicin (DOX) is a powerful anticancer agent with sever cardiotoxic side Keywords: metabolomics, cardiotoxicity, doxorubicin, cardioprotection, effect which limits the clinical use. Metformin (MET) is antihyperglycemic drug metformin. with potential cardioprotective effect via AMP-activated protein kinase (AMPK) (increases fatty acid oxidation, decreases the production of ROS, maintaining Correspondence: energy homeostasis and apoptosis). Metabolomics technology deals with Lubna Zuhair Abdul Karim systematic study of chemical fingerprints of metabolite profiles. Different *Pharmacist, Department of Pharmacology and Toxicology, College of Pharmacy, metabolic processes can be identified which will give information of any change Mustansiriyah University, M.Sc. program, Iraq. 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 *Corresponding author: Lubna Zuhair Abdul Karim email-address: four adult male wistar rats divided into four groups (6 animals each): control [email protected] 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. INTRODUCTION carbohydrates absorption, improving glucose peripheral Doxorubicin (DOX), is potent Satnrteipctaonmceyrcesdrug from u(7p,8)take and utilization and enhanced insulin sensitivity anthracycline(1f,2a)mily, have limited use because of its . It is approved to be effective in states associate(9d) with cardiotoxicity . It derived from bacteria, a insulin resistance, like polycystic ovary(1s0y) ndrome , also highly effective antitumor drug used for treatment it considered as an anticancer drug . Furthermore, different cancers like solid tumors, soft tissue sarcoma there are reports indicate (t2h)(1a1t) MET increases life span, and hematological malignancies, but its organs toxiciti(e3)s also it improves gut flora . MET produce its effects (cardio-, nephro-, and hepatotoxicity) limits its use . through (12,A13M) PK dependent and independent Cardiotoxicity induced by DOX is recognized by acute pathways . It is reported that this drug have cardiac dysfunction, chronic cardiomyopathy and finally cardioprotective effects in both hyperglycemic and lead to congestive heart failure (HF). There is different normoglycemic subjects. Models of experimental animal kinds of molecular mechanisms like oxidative stress, of isolated heart failure and myocardial infarction have inhibition of topoisomerase type II beta, alteration in shown that MET increases myocardium tolerance to energetics of mitochondria, the synthesis of protein and ischemic – reperfusion injury, decreases HF development nucleic acid inhibited, apoptosis induction, interaction after infraction by improving left ventricular ejection directly with the actin–myosin contractile proteins, fraction, improves the outcomes of patients with hypothesis of anthracycline metabolite, platelet activating advanced sy(s1t4o,1l5i)c HF and it may decrease DM factor, intracellular calcium, prostaglandin alterations complications .Through AMPK activation, MET able and etc., but the metabolic mechanism that occur and to reduce reactive oxygen specious (ROS)generation in cause toxicity has not yet been fully identified. Cellular animal models associated with HF, and protects energet(i4c–s6)have a critical role in cardiomyopathy induced myocardial cells from oxidative stress which is induced by DOX . by TNFα and H2O2, accordingly, MET act as antioxidant Metformin (MET) is an oral antihyperglycemic agent, agent and it have the ability to decrease lipid from biguanide family, widely used for diabetes peroxidation. These cardioprotection and antioxidant mellitus(DM) type 2 patients. It decrease intestinal 100 Systematic Reviews in Pharmacy Vol 12, Issue 3, Mar-Apr 2021 Metabolomics Of Metformin's Cardioprotective Effect In Acute Doxorubicin Induced- Cardiotoxicity In Rats Sample collection and preparation: properties suggest that ME(1T6,17a)ble to provide protection At the end of the against DOX- cardiotoxicity . experiment, the rats were anesthetized by intraperitoneal Metabolomics is systematic study of chemical administ(r30a)tion of 50 mg/kg ketamine and 5 mg/kg fingerprints of small-molecules complement xylazine . Blood samples were collected directly from (quantitatively and qualitatively) with in the biological the R(e31tr) o-orbital center by using heparinized capillary system (culture supernatants, cells, tissues, and body tubes , centrifuged at 2500x for 15 minutes for serum fluids) which is also called metabolom, or metabolite separation. The serum stored at -80°C for ELISA analysis. profiles. These metaboloms are associated with a variety After getting the blood sample, the heart is immediately of metab(o18l,i1c9) processes present in a cell, organ, or removed and washed with tap water then distilled water organism . Metabolomics is a developing method for and rapidly stored in liquid nitrogen. Small portion of the a particular phenotyping of the endogenous and heart tissue kept in 10% buffered neutral formalin to exogenous metabolite (usually, they are considered as prepare paraffin embedded blocks for histopathological cellular metabolic intermediates and products of (20l–e2s2)s Cdiaargdnioascism. etabolomics than 1 kDa in size) within a biological samples . Extraction of metabolomics: Metabolomics measures the response to perturbations like those related to the early diagnosis of d(2i3s–e2a5)se and for Exettraaclt.ion of metabolites the development and discovery of drugs . It gives from left ventricle of the heart tissue were done by the quantifiable information about body biochemi(c26a)l method described by Gregor (32) (2012) using a conditions in diseased and normal states . chloroform-methanol procedure . The stored heart Metabolomics aims to evaluate molecules having tissues were thawed at room temperature for 5 minutes differen(t24)physical properties such as, difference in then ~100 mg of left ventricle heart tissue crashed and polarity . Metabolomics has been conducted to analyze homogenized in 600 μL chloroform: methanol (1:2) DOX related toxicity biomarkers. Now, it is recognized as previously cooled , using ceramic mortar and pestle then a technique widely used to advance the toxicology, also it further pulverized in tissue homogenizer. Two hundred become a significant method in study the mechanism(2o7)f microliters of chloroform and then 200 μL deionized drugs that induce toxicity in metabolic level . water (HPLC grade) was added to each sample. Samples Metabolomics may identify cardiotoxicity early(2m) arkers, were vortexed for 10 seconds, then centrifuged for 20 and cardioprotective agents can be developed . Serum minutes at 4000 rpm in 4°C. The upper layer separated biomarkers such as cardiac troponin T, do not reflect and dried in a fume hood under a stream of nitrogen gas. specifically the damage that occur in myocardium. All extracted samples were stored at −20 ºC until Therefore, new b(i2o8)markers are needed for cardiac Dreeqruiivraetdi.zation of myocardium extracts: damage evaluation