Enoxaparin attenuates doxorubicin induced cardiotoxicity in rats via interfering with oxidative stress, inflammation and apoptosis

Abstract

BackgroundDoxorubicin (DOX) is commonly used in the treatment of many types of cancers but its cardiotoxicity is limiting its clinical use. Beyond its anticoagulant action, enoxaparin (ENX), a low molecular weight heparin, has been shown to exert multiple pharmacological actions including antioxidant, anti-inflammatory and antiapoptotic effects. Therefore, the current study aimed to assess if ENX could ameliorate cardiotoxicity induced by DOX.MethodsTwenty-one adult male Wistar albino rats were randomly allocated into three groups (n = 7 each) of control, receiving 0.9% saline (i.p.), DOX, receiving 2.5 mg/kg of DOX (i.p.) thrice weekly; and DOX + ENX, receiving ENX (250 IU/kg/day i.p.) and a DOX dose equivalent to that of the DOX only group.ResultsDOX-induced cardiotoxicity was indicated by marked increases in cardiac troponin I (cTnI) and severe histological lesions, which significantly correlated with cardiotoxicity, oxidative stress, inflammation and apoptosis markers, compared to controls. DOX group also showed elevations in malondialdehyde (MDA), a marker of oxidative stress, and reductions in total antioxidant capacity (TAC). Cardiac inflammatory markers including tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) and caspase-3, an apoptotic marker, were also elevated in the DOX group. DOX, however, did not significantly alter brain natriuretic peptide (BNP) levels. ENX significantly attenuated, but not completely reversed, DOX-induced cardiotoxicity through lowering cTnI and improving cardiomyopathy histopathological scores as compared to the DOX group. ENX also decreased MDA, increased TAC of rats’ heart to levels relatively comparable to control. Significant reductions in TNF-α, IL-1β and caspase-3 were also observed following ENX treatment relative to the DOX only group.ConclusionsCollectively, these results describe a cardioprotective effect for ENX against DOX-induced cardiotoxicity which is likely facilitated via suppression of oxidative stress, inflammation and apoptosis.

Liposomal Resveratrol and/or Carvedilol Attenuate Doxorubicin-Induced Cardiotoxicity by Modulating Inflammation, Oxidative Stress and S100A1 in Rats

“…Herein, the cardiotoxicity of DOX in rats was manifested by elevated serum levels of troponin-I, LDH and CK-MB, and was also confirmed by the histopathological examination, which revealed massive changes in the cardiac tissue, fragmentation and degeneration of cytoplasm and nuclei. These data were supported by previous studies where similar findings have been reported [40,52]. CAR, RES and LIPO-RES reduced the cardiotoxicity induced by DOX administration as evidenced by significant reduction of CK-MB, LDH and troponin-I levels and decreased myocardium degeneration in the histopathological findings that were in line with previous studies [40,53,54].…”

Cardioprotective Potential of Murraya koenigii (L.) Spreng. Leaf Extract against Doxorubicin-Induced Cardiotoxicity in Rats

“…Concentration of cTnI, NT-pro BNP, AST, and LDH activities were measured as serum biomarkers of myocardial injury. cTnI is considered as one of the most sensitive and commonly used biomarkers, and its release from the cardiomyocytes is proportional to the size and extent of cardiac tissue injury [42]. In the present study, doxorubicin control group showed a marked increase in cTnI concentration indicating that there is an extensive damage to the cardiac tissues in the presence of doxorubicin.…”

“…ese results were very much consistent with the results of the present study. Another study done by Shaker et al also reported that Wistar rats treated with 15 mg/kg cumulative dose of doxorubicin showed histological changes including congestion of myocardial vessels, myocardial swelling, myocardial fibers disorganization, cytoplasmic vacuolization, perinuclear vacuolization, and myofibrillar loss, and rats treated with enoxaparin showed mild to moderate score in tissue damage and displayed less cytoplasmic or perinuclear vacuolization and no myofibrillar loss [42].…”

Genistein protects against doxorubicin‐induced cardiotoxicity through Nrf‐2/HO‐1 signaling in mice model

“…Increased ROS activation and subsequent oxidative stress and inflammatory responses is key to DOX mediated effects on cardiomyocytes . Previous studies demonstrate that decline in antioxidant defense mechanisms involve in DOX‐induced cardiotoxicity . Increased NF‐κB activation has been previously reported during DOX‐induced cardiotoxicity .…”