The Role of Antioxidants in Ameliorating Cyclophosphamide-Induced Cardiotoxicity

Table 1

Effect of medicinal plants and isolates against cyclophosphamide-induced cardiotoxicity.

References	Animals used	Method and intervention	Major findings
Asiri [49]	Male Wistar albino rats	Rats were administered with the same doses of corn oil (control) and probucol (61 mg/kg/day, i.p), respectively, for one week before and one week after a single dose of CP (200 mg/kg, i.p.).	Probucol prevented the development of CP-induced cardiotoxicity by a mechanism related, at least in part, to its ability to increase mRNA expression of antioxidant genes and to decrease apoptosis in cardiac tissues with the consequent improvement in mitochondrial oxidative phosphorylation and energy production.
Avci et al. [61]	Female Wistar albino rats	Animals were treated with 100 mg/kg/day silymarin (SLY) by oral gavage for 14 days and 30 mg/kg/day CP intraperitoneally starting from the seventh day and 100 mg/kg/day curcumin (CUR) by gavage for 14 days plus 30 mg/kg/day CP intraperitoneally starting from the seventh day.	Concurrent administration of SLY and CUR with CP resulted significantly lower biochemical parameters and histopathological and immunohistochemical results than in the CP-only group.; It can be concluded that the natural antioxidant SLY and CUR might have protective effects against CP-induced cardiotoxicity and oxidative stress in rats.
Ayza et al. [62]	Either sex of Sprague Dawley rats	Animals were treated with a single dose of CP (200 mg/kg, i.p.) on the first day followed by hydromethanolic crude extract and solvent fractions of Croton macrostachyus for 10 days.	Croton macrostachyus reversed CP-induced elevations of cardiac troponin, ALT, AST, ALP, TC, and TG. These findings were further supported by histopathological findings.
Baniya et al. [63]	Male Wistar rats	Animals received a single dose of CP (200 mg/kg) on the first day followed by ethanolic extract of Citrus grandis (L.) Osbeck at 250 and 500 mg/kg, p.o. for 10 days.	Treatment with the extract reduced the serum biomarkers (CK-MB, ALT, AST, ALP, TC, and TG) and increased the tissue antioxidant level. Histopathology of heart tissue was also improved.
Bhatt et al. [64]	Either sex of Wistar rats	Cyclophosphamide (200 mg/kg, i.p.) toxicity was induced on day 1. Then, rats were treated with 100 mg/kg of mangiferin for 10 days.	Mangiferin treatment resulted in decrement of the serum cardiac biomarkers (AST, ALT, ALP, CK-MB, CK-NAC, and LDH).; Mangiferin increased tissue antioxidant levels (SOD, CAT, and GSH), and animals showed improvement in lipid profile, ECG parameters, histological score, and mortality.
Bjelogrlic et al. [65]	Female BalbC/NIH mice	Animals were treated with vitamin E (100 IU/kg, orally) 24 hr before single bolus doses of doxorubicin (10 mg/kg, intravenously), or doxorubicin and CP (150 mg/kg, i.p.).	Vitamin E in a single oral dose failed to inhibit acute cardiotoxic activity of doxorubicin but suspended further progression of the heart muscle damage over the time. On the contrary, vitamin E did not attain cardioprotection against doxorubicin and CP in combination.
Cetik et al. [66]	Sprague-Dawley rats	Carvacrol administration was started three days before the CP application and continued till the end of experiment (six days).	Carvacrol at both the doses increased the GSH levels close to the control group GSH levels.; Carvacrol at 5.0 and 10 mg/kg doses lowered the levels of serum ALT, AST, LDH, and CK-MB.; Reduced inflammation and lipid peroxidation in the heart tissue and increase of serum GSH and total antioxidant capacity (TAS) levels were found when carvacrol was applied.
Chakraborty et al. [67]	Either sex Wistar albino rats	Rats were subjected to CP toxicity with the dose of (200 mg/kg i.p.) on day first. Then, treated with green tea extract (GTE) along with hydrochlorothiazide.	GTE dose dependently reduced CP-induced myocardial toxicity. Green tea when combined with hydrochlorothiazide reduced the associated side effects and exhibited myocardial protection.
Chakraborty et al. [68]	Male Wistar albino rats	Rats were treated with combination of curcumin (100, 50, 25 mg/kg, p.o.) and piperine (20 mg/kg, p.o.) for 10 days. All treated groups were subjected to CP (200 mg/kg, i.p.) toxicity on day 1.	Piperine incorporation with the doses of 50 and 25 mg/kg with curcumin exhibited a significant beneficial effect compared to the curcumin alone-treated group.; Treatment with curcumin and piperine significantly modified the markers.
Conklin et al. [69]	Glutathione S-transferase (GSTP) wild-type (WT) and GSTP-P1/P2 null mice	To examine CP cardiotoxicity, WT and GSTP-null mice were treated with saline (control) or 100, 200, and 300 mg/kg CP.	According to the findings, myocardial GSTP levels are likely to be key determinants of CP cardiotoxicity. GSTP is a highly regulated enzyme that is readily induced by different environmental factors, diet constituents such as garlic organosulfur compounds, coffee, and chemopreventive agents such as selenocysteine conjugates. Therefore, GSTP induction by such agents could attenuate CP toxicity, and conversely, disturbed metabolic states such as obesity, which are associated with downregulation of GSTP, and could enhance the cardiotoxicity of CP treatment.
El-Agamy et al. [70]	Male Wistar rats	Cardiotoxicity was induced by single injection of CP (200 mg/kg, i.p.). Methyl palmitate (MP) was administered at two different dose levels (300 and 400 mg/kg) for 10 days before and 7 days after CP injection.	Animals treated with MP showed significant attenuation of ECG changes.; MP supplementation significantly lowered the elevated cardiac markers and improved cardiac lesions, which was more prominent at the higher dose.; MP treatment significantly decreased MDA content and enhanced the antioxidant parameters (SOD and GSH), and it significantly decreased the expression of TLR4 and NF-κB p65.; MP supplementation suppressed inflammatory cytokines (TNF-α and nitrite/nitrate) and reduced apoptosis.
Gado et al. [71]	Male Swiss albino rats	Curcumin (200 mg/kg, i.p.) was administered for 8 consecutive days followed by a single dose of CP (150 mg/kg, i.p.).	Serum LDH and CPK were decreased significantly with the curcumin administration.; Curcumin treatment significantly decreased MDA, NO(x), and restore GSH level in the cardiac tissue.; Histological alterations were also found to be improved.
Gunes et al. [72]	Male Sprague Dawley rats	Animals received respective selenium (Se) doses (0.5 or 1 mg/kg) for 6 days and then a single dose of CP administered on the sixth day. On day 7, the animals were sacrificed.	Based on microscopic evaluation, tissue damage was noticeably lower in CP plus Se groups. Additionally, 1 mg/kg Se was more protective than 0.5 mg/kg Se.; It can be concluded that Se can be a potential candidate to ameliorate CP-induced cardiotoxicity which may be related to its antioxidant activity.
Iqubal et al. [73]	Male Swiss albino mice	Animals were treated with nerolidol (NER) (200 and 400 mg/kg p.o.) and fenofibrate (FF) 80 mg/kg, p.o. for 14 days along with a single dose of CP 200 mg/kg i.p. on the 7th day.	NER 400 significantly reversed cardiotoxic effects of CP and showed cardioprotective activity which was comparable with FF 80.; However, NER 200 did not show significant cardioprotective activity.
Mansour and Hasan [74]	Male Wistar albino rats	Rats were pretreated with N-acetylcysteine (200 mg/kg) for 5 days; 1 hour after the last dose, rats were injected with CP (200 mg/kg).	Treatment with N-acetylcysteine significantly decreased serum levels of ALT, AST, CK, and LDH.; Decrease in the NOx, MDA levels and TNF- α, SOD, catalase, GSHPx, and GST levels were increased.
Mythili et al. [75]	Male Wistar albino rats	Rats received single injection of CP (200 mg/kg, i.p.) to induce cardiotoxicity, then followed by dl-α-lipoic acid treatment (25 mg/kg for 10 days).	Normalized lipid peroxidation and antioxidant defenses were observed in the dl-α-lipoic acid-treated rats.
Mythili et al. [76]	Male Wistar albino rats	Rats were injected with a single dose of CP (200 mg/kg, i.p) to induce cardiotoxicity, and then rats were treated with lipoic acid (25 mg/kg, orally for 10 days).	Treatment with lipoic acid reversed the abnormalities in the lipid levels and activities of lipid-metabolizing enzymes to near normalcy.
Mythili et al. [77]	Male Wistar albino rats	Rats received CP (200 mg/kg i.p.), which is immediately followed by lipoic acid (25 mg/kg orally) for 10 days.	Lipoic acid effectively reversed abnormal biochemical changes to near normalcy. Based on the results, lipoic acid showed a protective role of lipoic acid in CP-induced cardiotoxicity.
Nagi et al. [78]	Male Wistar albino rats	Rats received thymoquinone (50 mg/l in drinking water) for 5 days before a single dose of CP (200 mg/kg, i.p.) and continued thereafter until day 12. On day 13, animals were sacrificed.	Thymoquinone reversed CP-induced increase in serum CK-MB and LDH.; Complete reversal of the CP-induced increase in serum cholesterol, triglycerides, urea, and creatinine to the control values.; CP-induced increase in TBARS and NO(x) and a decrease in GSH, GPx, and CAT were reversed by thymoquinone supplementation.; Thymoquinone supplementation to CP-treated rats completely reversed the increase in TNF-α induced by CP.
Omole et al. [79]	Male Wistar rats	Rats were pretreated with 200 and 400 mg/kg/d Kolavorin, orally for 14 days followed by CP (50 mg/kg/d, i.p.) for 3 days.	Kolavorin pretreatment increased food consumption, body weight, and attenuated the biochemical and histological changes.; It was reported that kolavorin inhibited oxidative stress and preserved the activity of antioxidant enzymes.
Sekeroğlu et al. [80]	Male Swiss albino mice	After treatment with Viscum album and quercetin for 7 days, rats were administered CP (40 mg/kg, i.p) on days 8 and 9 of the experiment. Total treatment period was 10 days.	Treatments decreased the levels of antioxidant enzymes, glutathione-S-transferases; reduced glutathione and mitotic index were observed.; Quercetin completely and Viscum album partly ameliorated almost all of the examined parameters when given together with CP.
Senthilkumar et al. [81]	Male albino Wistar rats	Animals were cotreated with CP intraperitoneally dissolved in saline, in a dose of 150 mg/kg b.w. and different doses of squalene for the first 2 days, and squalene treatment was followed continuously, daily for 10 days up to the end of the experimental period.	Squalene oral treatment exerted protection to the heart, kidney, and liver at a dose of 0.4 ml/day/rat.; Histopathological examinations also confirmed the protective efficacy of squalene.; It can be concluded that squalene may be efficacious as a cytoprotectant in CP-induced toxicities.
Shalaby et al. [82]	Male Sprague-Dawley albino rats	Rats received Zingiber officinale 200 mg/kg/day orally followed by a single dose of CP (150 mg/kg i.p.).	Results showed significant improvement in the Zingiber officinale-treated group.; Based on their conclusion, the cardiotoxic effect of CP might be prevented by Zingiber officinale supplementation.
Shanmugarajan et al. [83]	Male Wistar rats	Rats were treated with the methanolic leaf extract of Ficus hispida Linn. for 10 consecutive days following CP-induced oxidative myocardial injury on the first day.	Treatment with Ficus hispida Linn. decreased serum cardiac biomarkers (CPK, LDH, AST, and ALT), and these were increased in the heart tissue.; Ficus hispida Linn. increased the levels of enzymic antioxidants (SOD, CAT, GPx, GSH, and GRx).
Song et al. [84]	Male ICR mice	Animals were injected with a single dose of CP (200 mg/kg i.p.) followed by the intragastric treatment with ferulic acid (FA) (50, 100 mg/kg) for 7 consecutive days.	FA significantly decreased the serum levels of cardiac biomarkers, IL-6, IL-1β, and TNF-α in CP-injected mice.; Additionally, FA effectively reduced the total numbers of WBCs, RBCs, platelets, and hemoglobin content. FA also attenuated the histological changes of the heart tissues caused by CP.; Moreover, western blot demonstrated that FA inhibited the phosphorylations of the NF-κB signaling pathway in CP-stimulated cardiac tissues.
Sudharsan et al. [85]	Male Wistar albino rats	Rats were injected with a single dose of CP (200 mg/kg, i.p) and treated with lupeol and lupeol linoleate (50 mg/kg).	Lupeol and its ester reversed alterations of serum lipoproteins and lipid fractions in both serum and cardiac tissue.; It was found that lupeol linoleate was more effective than lupeol.
Swamy et al. [86]	Male Wistar albino rats	Cardiotoxicity was induced by administering CP (200 mg/kg, i.p.) single injection. Saraca indica (200 and 400 mg/kg, p.o.) was daily for 10 days.	Treatment with Saraca indica reversed the status of cardiac biomarkers (CK, CK-MB, LDH, AST, ALT, and ALP) ECG, oxidative enzymes (GSH, SOD, and CAT), and lipid profile.
Todorova et al. [87]	Male Fischer 344 rats	After 2 d of prefeeding with glutamine (GLN) or glycine (GLY) by gavage, the rats were randomized into one of six groups receiving a lethal intraperitoneal dose of CP (450 mg/kg), a sublethal dose of CP (200 mg/kg), or saline (control).	The results showed that dietary GLN decreased cardiac necrosis and maintained normal cardiac GSH levels.; GLN protected against the acute cardiotoxic effects of CP and significantly improved the short-term survival after lethal and sublethal doses of CP.