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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 30  |  Issue : 4  |  Page : 1110-1116

Potential protective effects of trimetazidine and quercetin on isoprenaline-induced myocardial infarction in rats


1 Department of Clinical Pharmacology, Faculty of Medicine, El-Mansoura University, Mansoura, Egypt
2 Department of Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Department of Clinical Pharmacology, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission18-Mar-2017
Date of Acceptance24-May-2017
Date of Web Publication04-Apr-2018

Correspondence Address:
Doaa Z Mohammad Shebl
Department of Clinical Pharmacology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_183_17

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  Abstract 


Objective
The aim of this study was to investigate the protective effects of trimetazidine (TMZ), quercetin, and their combination on isoprenaline (ISO)-induced myocardial infarction (MI) in rats.
Background
ISO has been found to produce MI in large doses; it generates highly cytotoxic free radicals that produce severe damage to the myocardial membrane. Pretreatment with TMZ and quercetin reduce oxidative stress induced by ISO.
Materials and methods
Fifty adult rats were divided into five groups (n = 10). Group 1 (control) and group 2 (ISO-treated) received normal saline orally through a orogastric tube for 14 days and subcutaneously for the last 2 days. Group 3 (quercetin–ISO treated) received quercetin (50 mg/kg; orally), group 4 (TMZ–ISO treated) received TMZ (10 mg/kg; orally), and group 5 (quercetin-treated and TMZ–ISO treated) received combined drugs for 14 days. All groups except the control group received ISO (100 mg/kg; subcutaneously) in the last 2 days. Serum separation and estimation of highly sensitive cardiac troponin-I, C-reactive protein, serum malondialdehyde, and total serum antioxidant were performed. In addition, histopathological changes of the rat heart were assessed.
Results
The ISO-treated group showed increased serum levels of highly sensitive cardiac troponin-I, C-reactive protein, and malondialdehyde and decreased serum levels of total serum antioxidant, pathological picture of MI by hematoxylin and eosin staining, and negative myoglobin expression. These parameters improved better in the group receiving combined drugs compared with rats receiving TMZ or quercetin alone.
Conclusion
The combined treatment showed better synergistic antioxidant and anti-inflammatory effects compared with either treatment alone.

Keywords: isoprenaline, myocardial infarction, quercetin, trimetazidine


How to cite this article:
A. Yaseen AE, Shaban MI, El-Odemi MH, El-Fiky SR, Mohammad Shebl DZ. Potential protective effects of trimetazidine and quercetin on isoprenaline-induced myocardial infarction in rats. Menoufia Med J 2017;30:1110-6

How to cite this URL:
A. Yaseen AE, Shaban MI, El-Odemi MH, El-Fiky SR, Mohammad Shebl DZ. Potential protective effects of trimetazidine and quercetin on isoprenaline-induced myocardial infarction in rats. Menoufia Med J [serial online] 2017 [cited 2018 Oct 17];30:1110-6. Available from: http://www.mmj.eg.net/text.asp?2017/30/4/1110/229208




  Introduction Top


Myocardial infarction (MI) is an acute condition of necrosis of the myocardium that occurs because of an imbalance between coronary blood supply and myocardial demand[1]. The pathogenic mechanism of myocardial ischemic damage is not fully understood. Several studies indicate that its pathogenesis is mainly associated with oxidative stress, inflammatory response, calcium overload, and apoptosis[2]. Isoprenaline (ISO) is a β-adrenergic agonist that has been found to produce MI in high doses because of the generation of highly cytotoxic free radicals, leading to increased lipid peroxidation, altered activities of antioxidants, and cardiac enzymes producing infarct-like necrosis of the heart muscle[3]. Trimetazidine (TMZ) is a metabolic anti-ischemic agent with no hemodynamic effects. It inhibits the long-chain mitochondrial 3-ketoacyl coenzyme A thiolase enzyme in the mitochondria, thereby enhancing the metabolic shift from lipid oxidation to glucose oxidation[4]. The cardioprotective effect of TMZ can be explained by its direct cytoprotective actions, leading to decreased myocardial cell acidosis and calcium overload, preservation of intracellular adenosine triphosphate levels, elevation of the antioxidant capacity, and protection from oxygen-free radical-induced toxicity[5]. Quercetin is a natural antioxidant that acts by inhibiting lipid peroxidation through the inhibition of xanthine oxidase enzyme, and directly scavenging cytotoxic free radicals[6]. It has a potent anti-inflammatory activity as it inhibits inducible nitric oxide synthase expression[7]. Therefore, this study aimed to investigate the potential protective effects of pretreatment with TMZ (10 mg/kg) and quercetin (50 mg/kg) as well as their combination on ISO-induced MI in rats.


  Materials and Methods Top


This experiment was approved by the Ethics Committee for animal handling for research work at El-Menoufia University. Fifty, male, albino rats weighing 150–200 g were used in this study. Rats were divided into five groups (n = 10). Group 1 (control group) received 2 ml normal saline orally through an orogastric tube for the first 12 days, 2 ml normal saline orally through an orogastric tube, and 1 ml normal saline subcutaneously in the last 2 days. Group 2 (ISO-treated group) was treated similarly as group 1 for the first 12 days and with 2 ml normal saline orally through an orogastric tube and ISO powder Sigma Alderich (St. Louis, MO 63178, USA) at a dose of 100 mg/kg dissolved in 1-ml normal saline, injected subcutaneously once daily in the last 2 days[8]. Group 3 (quercetin–ISO-treated group) received quercetin powder Acros Company (Morris, New Jersey, USA) at a dose of 50 mg/kg dissolved in 2-ml normal saline orally by an orogastric tube once daily for 14 days[9] and ISO in the last 2 days as in group 2. Group 4 (TMZ–ISO-treated group) received TMZ powder (Servier Laboratories, Suresnes, Paris, France) at a dose of 10 mg/kg dissolved in 2-ml normal saline orally by an orogastric tube once daily for 14 days[10] and ISO for the last 2 days as in group 2. Group 5 (quercetin-treated and TMZ–ISO-treated group) received a combination of quercetin at a dose of 50 mg/kg and TMZ at a dose of 10 mg/kg dissolved in 2-ml normal saline orally by an orogastric tube once daily for 14 days and ISO in the last 2 days as in group 2. After the last treatment, within 24 h, blood samples were collected for serum separation and estimation of highly sensitive cardiac troponin-I (hs-cTn-I), C-reactive protein (CRP), serum malondialdehyde (MDA), and total serum antioxidants. In addition, histopathological changes of the rat heart were assessed by hematoxylin and eosin (H & E) and immunohistochemical staining to detect cardiac myoglobin.

Estimation of biochemical parameters

Collection of blood samples

Rats were anesthetized with diethyl ether. Venous blood samples were collected using heparinized capillary tubes from the retro-orbital plexus of rats. Hs-cTn-I was determined using an enzyme-linked immunosorbent assay kit that was obtained from BioMerieux (St. Louis, MO 63042, USA), for quantitative estimation of cTn-I in rat serum. Quantitative measurement of CRP in rat serum was carried out on Beckman Coulter AU analyzers (Beckman Coulter Inc., Brea, California, USA). Kits to estimate CRP were obtained from Beckman Coulter Inc. Estimation of serum MDA was through the spectrophotometric measurement of the color generated because of the reaction of thiobarbituric acid with MDA in acidic medium. Measurement of the total serum antioxidant capacity was performed by the reaction of antioxidants in the sample with a known amount of exogenously provided hydrogen peroxide. Kits for estimating both MDA and total serum antioxidants were obtained from Biodiagnostic (Cairo, Egypt).

Histopathological examination

Rats were anesthetized and killed by cervical decapitation. Sections from the heart of rats were collected and fixed in 10% formalin and prepared for H & E staining using the routine technique for histolopathological examination. In addition, immunohistochemical staining of cardiac myoglobin was carried out. The expression of myoglobin was detected using rabbit polyclonal myoglobin antibodies obtained from Scytek Laboratories (Logan, Utah, USA). Positive results for myoglobin were interpreted as brown discoloration of the nuclei of the epidermal cells. Myoglobin expression was assessed according to the intensity and distribution of brown discoloration of the nuclei of the epidermal cells.

Statistical analysis

Results were collected, tabulated, and statistically analyzed using an IBM personal computer and statistical package SPSS (version 20; SPSS Inc., Chicago, Illinois, USA) and MedCalc 13 for Windows (MedCalc Software BVBA, Ostend, Belgium). The results are expressed as mean ± SEM. One-way analysis of variance followed by Fisher's least significant difference multiple comparisons test was used for comparisons between means of different groups. A P value less than 0.05 was considered statistically significant.


  Results Top


Biochemical results

Serum levels of hs-cTn-I (pg/ml) in the ISO-treated group significantly increased compared with the control group (740.38 ± 49.10 vs. 41.56 ± 4.32, P1 <0.01). Serum levels of hs-cTn-I in the quercetin–ISO-treated group significantly decreased compared with the ISO-treated group (309.13 ± 13.47 vs. 740.38 ± 49.10, P2 <0.01). Serum levels of hs-cTn-I in the TMZ–ISO-treated group significantly decreased compared with the ISO-treated group (248.00 ± 12.04 vs. 740.38 ± 49.10, P3 <0.01). Serum levels of hs-cTn-I in the quercetin- and TMZ–ISO-treated group significantly decreased compared with the ISO-treated group (130.13 ± 13.88 vs. 740.38 ± 49.10, P4 <0.01). On the other hand, there was no significant difference between serum levels of hs-cTn-I in the quercetin–ISO-treated group compared with the TMZ–ISO-treated group (309.13 ± 13.47 vs. 248.00 ± 12.04, P5 =0.084). However, serum levels of hs-cTn-I significantly decreased in the quercetin-treated and TMZ–ISO-treated group compared with the quercetin–ISO-treated group and the TMZ–ISO-treated group (130.13 ± 13.88 vs. 309.13 ± 13.47 and 248.00 ± 12.04, P6 <0.01 and P7 <0.01, respectively) [Table 1] and [Figure 1].
Table 1: Comparison between the studied groups regarding serum levels of highly sensitive cardiac troponin-I (pg/ml), C-reactive protein (mg/ml), serum malondialdehyde (nmol/ml), and total serum antioxidant levels (mmol/l)

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Figure 1: Serum levels of highly sensitive cardiac troponin-I in pg/ml of the different studied groups. Data are expressed as mean ± SEM (n = 10). One-way analysis of variance followed by Fisher's least significant difference multiple comparisons test was used for comparisons between means of different groups.

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In addition, serum levels of CRP (mg/ml) in the ISO-treated group significantly increased compared with the control group (34.95 ± 2.29 vs. 2.05 ± 0.09, P1 <0.01). Serum levels of CRP in the quercetin–ISO-treated group significantly decreased compared with the ISO-treated group (14.33 ± 0.74 vs. 34. 95 ± 2.29, P2 <0.01). Serum levels of CRP of the TMZ–ISO-treated group significantly decreased compared with the ISO-treated group (7.13 ± 0.69 vs. 34. 95 ± 2.29, P3 <0.01). Serum levels of CRP in the quercetin-treated and TMZ–ISO-treated group significantly decreased compared with the ISO-treated group (4.55 ± 0.43 vs. 34. 95 ± 2.29, P4 <0.01). In addition, serum levels of CRP in the TMZ–ISO-treated group and the quercetin-treated and TMZ–ISO-treated group significantly decreased compared with the quercetin–ISO-treated group (7.13 ± 0.69 and 4.55 ± 0.43 vs. 14.33 ± 0.74, P5 <0.01 and P6 <0.01, respectively). On the other hand, there was no significant difference between serum levels of CRP in the TMZ–ISO-treated group compared with the quercetin-treated and TMZ–ISO-treated group (7.13 ± 0.69 vs. 4.55 ± 0.43, P7 =0.127) [Table 1] and [Figure 2].
Figure 2: Levels of serum C-reactive protein (CRP) in mg/ml of the different studied groups. Data are expressed as mean ± SEM (n = 10). One-way analysis of variance followed by Fisher's least significant difference multiple comparisons test was used for comparisons between means of different groups.

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Regarding oxidative stress markers, serum levels of MDA (nmol/ml) in the ISO-treated group significantly increased compared with the control group (7.93 ± 0.41 vs. 1.13 ± 0.04, P1 <0.01). Serum levels of MDA in the quercetin–ISO-treated group significantly decreased compared with the ISO-treated group (3.81 ± 0.18 vs. 7.93 ± 0.41, P2 <0.01). Serum levels of MDA in the TMZ–ISO-treated group significantly decreased compared with the ISO-treated group (2.53 ± 0.15 vs. 7.93 ± 0.41, P3 <0.01). Serum levels of MDA in the quercetin-treated and TMZ–ISO-treated group significantly decreased compared with the ISO-treated group (1.63 ± 0.04 vs. 7.93 ± 0.41, P4 <0.01). In addition, serum levels of MDA in the TMZ–ISO-treated group significantly decreased compared with the quercetin–ISO-treated group (2.53 ± 0.15 vs. 3.81 ± 0.18, P5 <0.01). In addition, serum levels of MDA in the quercetin-treated and TMZ–ISO-treated group significantly decreased compared with the quercetin–ISO-treated group and the TMZ–ISO-treated group (1.63 ± 0.04 vs. 3.81 ± 0.18 and 2.53 ± 0.15, P6 <0.01 and P7 <0.01) [Table 1] and [Figure 3]a.
Figure 3: (a) Levels of serum malondialdehyde (MDA) (nmol/ml) in the different studied groups. (b) Levels of total serum antioxidants (mmol/l) in the different studied groups. Data are expressed as mean ± SEM (n = 10). One-way analysis of variance followed by Fisher's least significant difference multiple comparisons test was used for comparisons between means of different groups.

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However, serum levels of total antioxidants (mmol/l) in the ISO-treated group significantly decreased compared with the control group (0.70 ± 0.07 vs. 2.96 ± 0.21, P1 <0.01). Serum levels of total antioxidants in the quercetin–ISO-treated group significantly increased compared with the ISO-treated group (1.24 ± 0.05 vs. 0.70 ± 0.07, P2 <0.01). Serum levels of total antioxidants in the TMZ–ISO-treated group significantly increased compared with the ISO-treated group (1.69 ± 0.61 vs. 0.70 ± 0.07, P3 <0.01). Serum levels of total antioxidants in the quercetin-treated and TMZ–ISO-treated group significantly increased compared with the ISO-treated group (2.18 ± 0.72 vs. 0.70 ± 0.07, P4 <0.01). In addition, serum levels of total antioxidants in the TMZ–ISO-treated group significantly increased compared with the quercetin–ISO-treated group (1.69 ± 0.61 vs. 1.24 ± 0.05, P5 <0.01). In addition, serum levels of total antioxidants in the quercetin-treated and TMZ–ISO-treated group significantly increased compared with the quercetin–ISO-treated group and TMZ–ISO-treated group (2.18 ± 0.7 vs. 1.24 ± 0.05 and 1.69 ± 0.61, P6 <0.01 and P7 <0.01) [Table 1] and [Figure 3]b.

Histopathological results

Regarding histopathological examination of the heart by H and E in the different studied groups, sections from the control group showed normal cardiac muscle showed with fusiform cells with eosinophilic cytoplasm and spindle-shaped nucleus [Figure 4]a, whereas the ISO-treated group showed an area of infarction that revealed homogenous pink structureless material with karyorrhexis (fragmented nuclei) [Figure 4]b. Rats pretreated with quercetin in the quercetin–ISO-treated group showed improvement where there was moderate cardiac muscle changes in the form of cardiac muscle swelling and cytoplasmic edema [Figure 4]c. Rats pretreated with TMZ in the TMZ–ISO-treated group showed better improvement than rats receiving quercetin, where mild cardiac muscle degeneration revealed myocyte vacuoles, which are large, cleared, intracellular spaces, probably containing water [Figure 4]d. Rats receiving combined drugs in the quercetin-treated and TMZ–ISO-treated group showed more marked improvement compared with rats receiving quercetin or TMZ alone where there is minimal cardiac muscle degeneration in the form of cloudy swelling of cardiac muscles with pale eosinophilic cytoplasm [Figure 4]e.
Figure 4: Histopathological examination of the heart by hematoxylin and eosin staining in the different studied groups: (a) sections from the control group showed normal cardiac muscle with skewed fusiform cells with an eosinophilic cytoplasm and spindle-shaped nucleus. (b) Sections from the isoprenaline (ISO)-treated group showed an area of infarction with homogenous pink structureless material with karyorrhexis (fragmented nuclei). (c) Sections from rats pretreated with quercetin showed moderate cardiac muscle changes in the form of cardiac muscle swelling and cytoplasmic edema. (d) Sections from the trimetazidine (TMZ)–ISO-treated group showed mild cardiac muscle degeneration with myocyte vacuolization – these were large, clear, intracellular spaces, probably containing water. (e) Sections from the quercetin-treated and TMZ–ISO-treated group showed minimal cardiac muscle degeneration in the form of cloudy cardiac muscle swelling with a pale esinophilic cytoplasm.

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Immunohistochemistry revealed that sections from the control group showed positive myoglobin expression in cardiac muscle, where the brown pigment strongly appeared in both the nucleus and the cytoplasm of the cardiac muscles, indicating that the viable cells retained myoglobin [Figure 5]a, whereas the ISO-treated group showed negative myoglobin expression in cardiac muscles. These tissues did not stain, indicating that they did not contain myoglobin [Figure 5]b. Rats pretreated with quercetin in the quercetin–ISO-treated group showed improvement – there was mild myoglobin expression in cardiac muscles, and the brown pigment mildly appeared in both the nucleus and the cytoplasm of the cardiac muscles [Figure 5]c. Rats pretreated with TMZ in the TMZ–ISO-treated group showed better improvement compared with rats that received quercetin – there was moderate myoglobin expression, and the brown pigment moderately appeared in both the nucleus and the cytoplasm of the cardiac muscles [Figure 5]d. Rats that received both drugs together in the quercetin-treated and TMZ–ISO-treated group showed more marked improvement compared with rats that received quercetin or TMZ alone – there was strong myoglobin expression, and the brown pigment strongly appeared in both the nucleus and the cytoplasm of the cardiac muscles [Figure 5]e.
Figure 5: Immunohistochemical staining of cardiac myoglobin in the different studied groups: (a) Sections from the control group showing positive myoglobin expression in cardiac muscle, where the brown pigment strongly appears in both the nucleus and the cytoplasm of the cardiac muscles, indicating that the viable cells retained myoglobin. (b) Sections from the isoprenaline (ISO)-treated group showed negative myoglobin expression in cardiac muscles; these tissues did not stain, indicating that they contained no myoglobin. (c) Sections from rats pretreated with quercetin showed mild myoglobin expression in cardiac muscle; the brown pigment mildly appeared in both the nucleus and the cytoplasm of the cardiac muscles. (d) Sections from rats pretreated with trimetazidine showed moderate myoglobin expression; the brown pigment moderately appeared in both the nucleus and the cytoplasm of the cardiac muscles. (e) Sections from rats that received both drugs showed strong myoglobin expression; the brown pigment strongly appeared in both the nucleus and the cytoplasm of the cardiac muscles.

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  Discussion Top


In the present study, MI was induced in rats by subcutaneously injecting 100 mg/kg ISO hydrochloride dissolved in saline once daily for 2 successive days[8]. It has been reported that ISO administration in high doses to animals produces MI as it generates highly cytotoxic free radicals, causing marked lipid peroxidation and altered activities of cardiac enzymes and antioxidants, resulting in MI[9]. The pathophysiological and morphological changes in the myocardium after ISO administration have been shown to be similar to those occurring during MI in humans[11]. The present study was undertaken to investigate the potential protective effects of pretreatment with TMZ (10 mg/kg) and quercetin (50 mg/kg) as well as their combination on ISO-induced MI in rats. In the present study, the ISO-treated group showed a significant increase in serum MDA and significant decrease in total serum antioxidants compared with the control group. These results are in agreement with Kannan and Quine[12] who reported that ISO increased cardiac MDA and decreased reduced glutathione (GSH) content compared with the control group. In addition, these results are in agreement with Liu et al.[13] who found that thiobarbituric acid reactive substances, as an indicator of lipid peroxidation, have been significantly elevated in cardiac tissues and there is significant reduction in plasma superoxide dismutase, glutathione peroxidase, catalase, and GSH in the ISO-treated group compared with the control group. However, these results are not in agreement with Mladenka et al.[14] who reported that plasma MDA was nonsignificantly increased in the ISO-treated group compared with the control group. ISO-generated free radicals cause peroxidation of membrane-bound polyunsaturated fatty acids, leading to destruction of the structural and functional integrity of the myocardium with subsequent changes in membrane permeability[15]. Myocyte death or changed membrane permeability causes the cytosolic contents to pass onto systemic circulation, where they may be detected as markers of ischemic heart disease. This accounts for significant elevation of serum levels of cTn-I following ISO administration in the ISO-treated group compared with the control group. This result is in agreement with Zaafan et al.[9] as well as with Kannan and Quine[12]. Inflammation is a key process involved in mediating myocardial tissue destruction. In the present study, ISO produced a significant increase in serum levels of CRP in the ISO-treated group compared with the control group. This result is in agreement with the study by Tawfik et al.[16].

Histopathological examination by H and E staining of the ISO-treated group showed an area of infarction with a homogenous pink structureless material with karyorrhexis (fragmented nuclei) in comparison with the normal histological morphology of the control group. This result is in agreement with Kannan and Quine[12] who reported that histopathological examination of ISO-treated rats showed infiltration of inflammatory cells with degeneration of cardiac muscles. By immunohistochemistry, the ISO-treated group showed negative myoglobin expression in cardiac muscles; these tissues did not stain, demonstrating that they contained no myoglobin in comparison with the control group that showed positive myoglobin expression in cardiac muscles where the brown pigment strongly appears in both the nucleus and the cytoplasm of the cardiac muscles, demonstrating that the viable cells retained myoglobin. This result is in accordance with Block et al.[17] who found similar results in dogs and human tissues.

In the quercetin–ISO-treated group, pretreatment with quercetin showed a marked protection against ISO-induced myocardial damage, in which quercetin significantly decreased serum levels of MDA and significantly increased total serum antioxidants. These results are in agreement with Panda et al.[18] who reported that quercetin produced a significant decrease in cardiac MDA and increased GSH content. These beneficial effects of quercetin could be attributed to its antioxidant properties, which are mainly owing to its ability to increase GSH, antioxidant enzyme levels, and scavenge lipid peroxides[13]. In addition, quercetin significantly decreased serum levels of cTn-I. These findings are in agreement with Zaafan et al.[9] and with Liu et al.[13]. The anti-inflammatory effect of quercetin was apparent by the significant decrease in serum levels of CRP. This result is in agreement with Kleemann et al.[19].

Regarding histopathological examination by H & E of rats pretreated with quercetin, improvement was noticed where there were moderate cardiac muscle changes in the form of cardiac muscle swelling cytoplasmic edema. This result is in agreement with Zaafan et al.[9], and withLiu et al.[13]. By immunohistochemistry, quercetin increased myoglobin expression in cardiac muscles that showed mild myoglobin expression.

In the TMZ–ISO-treated group, pretreatment with TMZ produced a marked protection against ISO-induced myocardial injury, in which TMZ significantly decreased serum levels of MDA and significantly increased total serum antioxidants. These results are in agreement with Meng et al.[20] who found that TMZ prevented elevation of MDA caused by ISO treatment. The beneficial effects of TMZ on myocardial injury are associated with the limitation of lipid peroxidation in the heart. In addition, these results are in agreement with Iskesen et al.[21] who reported that pretreatment with TMZ reduces MDA production and preserves endogenous antioxidant capacity by increasing levels of superoxide dismutase and glutathione peroxidase in patients during coronary interventions. These beneficial effects of TMZ can be attributed to its antioxidant properties as it increases the endogenous antioxidant capacity and protects against oxygen-free radicals. In addition, TMZ significantly decreases serum levels of cTn-I. This result is in agreement with Bonello et al.[22] who reported that pretreatment with TMZ produced a significant reduction in cTn-I levels in patients with acute coronary syndrome. The anti-inflammatory effect of TMZ was obvious by the significant decrease in serum levels of CRP. This result is in agreement with Pudil et al.[23] who reported that in a population with MI the TMZ group showed a significant reduction in plasma CRP.

Regarding histopathological examination by H & E staining of rats pretreated with TMZ, a marked improvement was noticed where there was mild cardiac muscle degeneration. This result is in agreement with Meng et al.[20] who found that pretreatment with TMZ prevented the ISO-induced histological destruction, indicating that TMZ produces a pronounced protective effect on myocardial injury. By immunohistochemistry, TMZ increased myoglobin expression in cardiac muscles that showed moderate myoglobin expression.

In the quercetin-treated and TMZ–ISO-treated group, pretreatment with quercetin and TMZ together produced a marked protection against ISO-induced myocardial damage, in which the combined drugs significantly decreased serum levels of MDA and significantly increased total serum antioxidants. In addition, combined drugs significantly decreased serum levels of cTn-I. The anti-inflammatory effects of quercetin and TMZ together were apparent by the significant decrease in serum levels of CRP. Regarding histopathological examination by H & E of rats pretreated with combined drugs, a marked improvement was noticed where there was only minimal or even no detectable cardiac muscle swelling and cytoplasmic edema. By immunohistochemistry, combined drugs increased myoglobin expression in cardiac muscles that showed strong myoglobin expression.

In the present study, comparison between the three treated groups regarding biochemical parameters and histopathological examination showed that these parameters improved better in the group pretreated with quercetin and TMZ together followed by the group pretreated with TMZ alone followed by the group pretreated with quercetin alone. Therefore, the present study revealed that pretreatment with quercetin and TMZ together produced more marked cardioprotective effects compared with pretreatment with TMZ or quercetin alone. Such effects can be explained by the antioxidant and anti-inflammatory potentials of both quercetin and TMZ that were more apparent when administered in combination.


  Conclusion Top


Both quercetin and TMZ reduced myocardial oxidative stress and inflammation induced by ISO. Combined treatment showed better synergistic antioxidant and anti-inflammatory effects compared with either treatment alone. Therefore, quercetin can be regarded as a promising natural cardioprotective agent in MI alone or when combined with TMZ.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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