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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 35  |  Issue : 4  |  Page : 1872-1878

Effect of diltiazem and quercetin on monosodium glutamate-induced hepatic dysfunction in rats


1 Department of Medical Physiology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission14-May-2022
Date of Decision03-Aug-2022
Date of Acceptance07-Aug-2022
Date of Web Publication04-Mar-2023

Correspondence Address:
Hesham Abdel-Razek
Shebin el-kom, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_268_22

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  Abstract 


Background
Calcium-channel blockage effect of diltiazem and antioxidant effect of quercetin may combat against monosodium glutamate (MSG)-induced liver dysfunction in rats.
Objective
The aim was to study the protective effects of diltiazem and quercetin administration on possible MSG-induced changes of liver functions in adult rats.
Methods
Fifty adult male Wistar rats were divided into five equal groups: control group (C), MSG-treated group (G), diltiazem and MSG-treated group (DG), quercetin and MSG-treated group (QG), and combined diltiazem, quercetin, and MSG-treated group (DQG). The duration of concomitant administration of treatments was 6 weeks. Then, fasting blood samples were collected to measure serum alanine transaminase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, and serum malondialdehyde. Last, antioxidant activities of glutathione peroxidase and superoxide dismutase were measured in liver tissue homogenate. Hematoxylin and eosin staining and Bcl2 immunohistochemical staining of rat liver was assessed for detection of structural changes and apoptosis, respectively.
Results
In DG, QG, and DQG groups, alanine transaminase, aspartate aminotransferase, gamma-glutamyl transferase, and malondialdehyde in serum were significantly lower (P < 0.001) than G group denoting significant improvement in hepatic parameters and oxidative stress. In addition, these three groups caused significant increase (P < 0.001) in hepatic tissue glutathione peroxidase and superoxide dismutase activities. Hematoxylin and eosin staining and Bcl2 immunohistochemical staining of rat liver of these three groups showed significant decrease in structural damage and apoptosis when compared with G group.
Conclusion
Diltiazem and quercetin reduce hepatic oxidative stress and tissue damage induced by MSG, and improve liver dysfunctions, with better effect of their combination.

Keywords: diltiazem, liver, monosodium glutamate, quercetin, rats


How to cite this article:
Abdel-Razek H, El-Rebey HS, Youssef GS, Donia SS, Adel MM, Motawea SM. Effect of diltiazem and quercetin on monosodium glutamate-induced hepatic dysfunction in rats. Menoufia Med J 2022;35:1872-8

How to cite this URL:
Abdel-Razek H, El-Rebey HS, Youssef GS, Donia SS, Adel MM, Motawea SM. Effect of diltiazem and quercetin on monosodium glutamate-induced hepatic dysfunction in rats. Menoufia Med J [serial online] 2022 [cited 2024 Mar 28];35:1872-8. Available from: http://www.mmj.eg.net/text.asp?2022/35/4/1872/371004




  Introduction Top


Monosodium glutamate (MSG) is the sodium salt of the nonessential amino acid –glutamic acid. It is commonly consumed as a flavor enhancer or food additive. The unique flavor of this compound is umami taste [1]. Chronic exposure of rodents to MSG is manifested by increased oxidative stress, cytotoxicity, immunosuppression, obesity, neurobehavioral abnormalities, and tissue damage in vivo and in vitro. MSG intake is also associated with a significant increase in ABP as the glutamate in it has a vasoconstrictive effect on blood vessels due to its action as a calcium-channel opener [2]. Diltiazem is a nondihydropyridine L-type calcium-channel blocker used in the treatment of hypertension, angina pectoris, and arrhythmia [3]. Diltiazem probably prevents the hypertensive side effect of MSG by reducing the intracellular calcium overload through blocking the calcium channels in the cell membrane and reducing the permeability of cell membrane for calcium ions. Pretreatment with diltiazem prevents the effects of MSG on hypothalamus [4] and ovaries [5] of rats. Quercetin is a flavonol found in many fruits, vegetables, leaves, and grains. It can be used as an ingredient in supplements, beverages, or foods. It has protective effects on cell function in vivo and in vitro[6]. Quercetin has antioxidant, cancer prevention, DNA protection, anti-inflammatory actions, and cardioprotective activity [7].

So, this work aimed to study the calcium-channel blockage effect of diltiazem and the antioxidant effect of quercetin on MSG-induced liver dysfunction in rats.


  Methods Top


Ethics statement: The experimental protocol was approved by the local ethics committee of Faculty of Medicine, Menoufia University. Animals were housed in Medical Experimental Research Laboratory, Faculty of Medicine, Menoufia University, Egypt, and were treated in accordance with Guide for the Care and Use of Laboratory Animals (eighth edition, National Academies Press) (NIH Publication No 85-23, Revised 1996).

Animals: In total, 50 adults male Wistar albino rats (each weighing 150–180 gm) were randomly divided into five equal experimental groups (10 animals each): control (C) group: rats were given 0.5 ml of distilled water by esophageal gavage along with regular diet and free access to water, once daily for 6 weeks. MSG-administered (G) group: rats were given MSG (Ajinomoto Co. Inc., Tokyo, Japan) in a dose of 3 g/kg body weight, dissolved in 0.5 ml of distilled water, by esophageal gavage, once daily for 6 weeks along with regular diet and free access to water [8]. Diltiazem-treated MSG-administered (DG) group: rats were given MSG as in G group together with diltiazem (Egyptian International Pharmaceutical Industries Co., Dokki, Giza, Cairo, Egypt) in a dose of 10 mg/kg body weight/day [9] by esophageal gavage, once daily for 6 weeks. Quercetin-treated MSG-administered (QG) group: quercetin (Sigma-Aldrich Chemical Company, Steinheim, Germany) was given in a dose of 10 mg/kg body weight [10], together with the same dose of MSG taken in G group, by esophageal gavage, once daily for 6 weeks. Combined diltiazem and quercetin-treated, MSG-administered (DQG) group: rats were administered MSG as in G group, and were given diltiazem as in DG group concomitantly with quercetin as in QG group, once daily for 6 weeks.

At the end of the experimental period, rats were fasted overnight, and retro-orbital blood samples were collected for further analysis of serum alanine transaminase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and MDA levels (Biodiagnostic Company, Egypt). Last, rats of all groups were sacrificed and the liver was extracted and weighed to calculate its relative body weight. Part of the liver was homogenized and the antioxidant activities of glutathione peroxidase (GPx) and superoxide dismutase (SOD) enzymes (Biodiagnostic Company) were measured. Another part of it was fixed in 10% formalin saline for histopathological examination by light microscope using hematoxylin and eosin and Bcl2-immunohistochemical staining (Dako, Carpinteria, CA).

Serum biochemical analysis: blood sampling: venous blood samples were collected from the retro-orbital venous plexus, using a fine heparinized capillary tube introduced into the medial epicanthus of the rat's eye [11]. Two milliliters of blood were collected in a clean graduated centrifuge tube, left for clotting at room temperature in a water bath for 10 min, and then centrifuged at 4000 rotations per minute (rpm) for 10 min. Serum was collected and frozen at −20°C until needed for subsequent analysis.

Assessment of liver functions: Serum AST and ALT activities were evaluated using the method described by Reitman and Frankel [12] and serum GGT was assessed according to Szewczuk et al. [13].

Colorimetric estimation of serum MDA: was done using thiobarbituric acid reactive substance for measuring the peroxidation of fatty acids [14].

Homogenization of the liver [14]: the excited right lobe of the liver was perfused with saline solution to remove any red blood cells and clots, and it was separated into two parts, one part was homogenized in 5 ml of cold phosphate-buffered saline solution, pH 7.4, per gram tissue (for estimation of GPx) and the other part in 5 ml of cold potassium phosphate buffer, pH 7.0, per gram tissue (for estimation of SOD). The homogenized tissue was centrifugated at 4000 rpm for 15 min, and the supernatant fluid was removed and stored at −80°C for biochemical assays.

Estimation of glutathione peroxidase activity in the liver: The assay was an indirect measure of the activity of cellular GPx (c-GPx). Oxidized glutathione (GSSG), produced upon reduction of an organic peroxide by c-GPx, was recycled to its reduced state by the enzyme glutathione reductase [15].

Estimation of superoxide dismutase activity in the liver: colorimetric estimation of SOD activity relies on the ability of the enzyme to inhibit the phenazine methosulfate-mediated reduction of nitro blue tetrazolium dye [16].

Histopathological examination of the liver [17]: the left lobe of the liver was removed, fixed in 10% formalin solution, and sent to Pathology Department, Faculty of Medicine, Menoufia University, to be processed as follows: liver tissue from each rat was placed in 10% formaldehyde for 2 h, removed and placed in a new formaldehyde solution for 24 h before being dehydrated using ethanol (70% for 24 h, 90% for 1 h, and 100% for 1 h), then cleaned in xylene, and embedded in paraffin. Coronal sections were cut with a microtome (Leica RM 2025, Rankin Biomedical Corporation, Makey Rd Holly, United states of America) at 4-μm thicknesses, mounted on glass slides, and stained with the routine hematoxylin and eosin technique.

Bcl2 immunohistochemical staining [18]: liver sections were immunohistochemically stained to assess the immunoexpression of antiapoptotic protein (Bcl2). Paraffin sections of tissues were cut at 4-μm thickness on positively charged slides. Sections were incubated with a monoclonal antibody against Bcl2 (Dako), concentrated with a dilution of 1: 200. Cells displaying brown staining were considered positive for Bcl2 expressions. Cell's expression was graded subjectively for intensity of staining and for the percentage of expression as follows:

Intensity scoring was ranked as 0: no staining, +1: mild intensity, +2: moderate intensity, and +3: strong intensity. The percentage of expression was also assessed as numerical results (%) [19]. Then, H-score system was applied according to Ilić et al. [20], where both the intensity and percentage of positivity were considered using the following formula: H score=(3×% of strong intensity)+(2×% of moderate intensity)+(1×% of mild intensity). The maximum score was 3 × 100 = 300.

Statistical analysis

The results were statistically analyzed and expressed as mean ± SD using the Statistical Package for the Social Sciences version 22 (SPSS Inc., Chicago, IL). The statistical significance between the means of different groups was analyzed using the One-way analysis of variance test, followed by Tukey's post-hoc test. The level of statistical significance was set at P less than or equal to 0.05 [21].


  Results Top


Biochemical results

Serum ALT and AST activities of G group were 58.6 ± 2.1 and 47 ± 3.4 U/L, respectively, which were significantly higher than the corresponding values in C group (14.8 ± 1.7 and 11.6 ± 1.6 U/L, respectively). Values of serum ALT and AST were 34.6 ± 3.7 and 25.3 ± 2.5 U/L, respectively, in DG group, and 33.5 ± 2.7 and 24 ± 3.2 U/L, respectively, in QG group, which were significantly lower than the corresponding values in G group, but they were still significantly higher than those in C group. In DG group, values of ALT and AST were insignificantly changed when compared with the corresponding values in QG group. In DQG group, average values of ALT and AST were 20.6 ± 2.1 and 20.6 ± 2.1 U/L, respectively, which were significantly less than the corresponding values in G, DG, and QG groups, but they were still significantly more than those in C group. Serum GGT activities of G group were 223.9 ± 5.6 U/L, which was significantly higher than the corresponding value in C group (120 ± 4.4 U/L). The value of GGT was 165.04 ± 3.4 U/L in DG group, and 168.08 ± 3.05 U/L in QG group, which were significantly lower than the corresponding value in G group, but they were still significantly higher than in C group. Average values of GGT in DG and QG groups showed insignificant variation when compared with each other. In DQG group, the value of GGT was 126.6 ± 4.1 U/L, which was significantly lower than the corresponding values in G, DG, and QG groups, but it was still significantly higher than those in C group [Table 1].
Table 1: Serum alanine transaminase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) (U/L) in all the studied groups

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Serum MDA level of G group was 88.1 ± 8.8 nmol/ml, which was significantly higher than the corresponding value in C group (19.8 ± 3.2 nmol/ml). Values of MDA levels were 48.3 ± 9.6 and 51.3 ± 8.1 nmol/ml in DG and QG groups, respectively, which were significantly lower than the corresponding value in G group, but they were still significantly higher than the corresponding value in C group. Values of MDA in DG and QG groups showed insignificant change when compared with each other. In DQG group, serum MDA level was 28.6 ± 2.6 nmol/ml, which was significantly lower than the corresponding values in G, DG, and QG groups, while it was insignificantly changed when compared with that in C group. Liver SOD activity of G group was 2.5 ± 0.64 U/g tissue, which was significantly lower than the corresponding value in C group (10.7 ± 0.9 U/g tissue). The activities of SOD in liver tissue were 6.9 ± 0.67 and 7.2 ± 0.87 U/g tissue in DG and QG groups, respectively, which were significantly higher than the corresponding value in G group, but they were still significantly lower than that in C group. Liver SOD activity was significantly lower in DG group than that in QG group. In DQG group, SOD activity was 10.4 ± 1.6 U/g tissue, which was significantly higher than the corresponding values in G, DG, and DQG groups, while it was insignificantly changed, when compared with that in C group. Liver GPx activity of G group was 41.5 ± 2.9 U/g tissue, which was significantly lower than the corresponding value in C group (88.3 ± 5.9 U/g tissue). GPx activities in the liver were 74.03 ± 1.7 and 77.4 ± 1.3 U/g tissue in DG and QG groups, respectively, which were significantly higher than the corresponding value in G group. Insignificant change was observed when comparing liver GPx activity in DG group with that in QG one. In DQG group, liver GPx activity was 88.6 ± 6.6 U/g tissue, which was significantly more than the corresponding values in G, DG, and QG groups, while it was insignificantly changed when compared with that in C group [Table 2].
Table 2: Serum malondialdehyde (MDA) level (nmol/ml), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities (U/g tissue) in the liver tissue homogenate in all the studied groups

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Histological and immunohistochemical results

Rat liver sections in C group showed normal appearance [Figure 1]a with strong diffuse Bcl2 staining [Figure 2]). Sections of rat liver of G group showed excess mononuclear inflammatory infiltrate around a congested branch of portal vein in liver tissue [Figure 1]b with negative Bcl2 staining [Figure 2]b. While DG and QG groups exhibited mild mononuclear inflammatory infiltrate around a mildly dilated branch of portal vein in liver tissue [Figure 1]c, [Figure 1]d with mild patchy Bcl2 staining [Figure 2]c, [Figure 2]d. Liver sections of DQG group exhibited mild mononuclear inflammatory infiltrate around a mildly dilated branch of portal vein [Figure 1]e with moderate patchy Bcl2 staining [Figure 2]e.
Figure 1: Normal appearance of rat liver in C group (a) [hematoxylin and eosin (H and E), ×200]. G group showed excess mononuclear inflammatory infiltrate (arrows) around a congested branch of portal vein (star) in liver tissue (b) (H and E, ×100), DG group exhibited mild mononuclear inflammatory infiltrate (arrow) around a mildly dilated branch of portal vein (star) in liver tissue (c) (H and E, ×200), QG group exhibited mild mononuclear inflammatory infiltrate (arrow) in the portal tract of liver tissue (d), (H and E, ×200), and DQG group showed reduced the monosodium glutamate-induced histopathologic changes in liver (e) (H and E, ×200).

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Figure 2: Strong/diffuse Bcl2 staining in rat liver sections of C group (a) [immunohistochemistry (IHC)×200], G group showed negative Bcl2 staining in rat liver (b) (IHC × 100), DG group exhibited mild/patchy Bcl2 staining in liver (c) (IHC × 200), QG group showed mild/patchy Bcl2 staining in rat liver (d) (IHC × 200), and DQG group showed moderate Bcl2 staining in rat liver (e) (IHC × 200).

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H score of Bcl2 immunostaining in liver of G group was 2.5 ± 0.4, which was significantly lower when compared with the corresponding values in C group, which was 165 ± 2. It was 43.3 ± 3 in DG group, which was insignificantly changed when compared with the corresponding value in G, group while it was significantly lower when compared with the corresponding value in C group. In QG group, it was 63.3 ± 4.3, which was insignificantly changed when compared with the corresponding values in G and DG groups, while it was significantly lower when compared with the corresponding value in C group. In DQG group, it was 101.6 ± 4.5, which was significantly higher when compared with the corresponding value in G group, while it was insignificantly changed when compared with the corresponding values in C, DG, and QG groups [Table 3].
Table 3: H score of Bcl2 immunostaining of the liver in all the studied groups

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  Discussion Top


The present study showed an impairment in the liver functions of rats after MSG administration, as demonstrated by elevation in the serum activities of ALT, AST, and GGT, that was associated with oxidative stress that was indicated by increased serum MDA with reduction in the activities of the antioxidant enzymes, GPx and SOD, in the liver. These results coincided with those of Khayal et al. [22], who revealed that administration of MSG for 6 weeks induced significant elevation in the mean values of serum ALT, GGT, and hepatic MDA with significant reduction in the mean values of hepatic GPx.

Another study by Bełtowski et al.[23] reported that SOD activity was decreased and GPx was increased in MSG-treated rats, with a net decrease in SOD/GPx ratio that favors O2¯ formation (decomposed by SOD) rather than H2O2 (formed by SOD and decomposed by GPx). It has been suggested that these alterations in antioxidant enzymes may limit oxidative damage because O2¯ has a shorter half-life, is less membrane-permeable, and thus less harmful than H2O2. Shrestha et al.[24] also reported that MSG induced an increase in the liver-enzyme markers, ALT, AST, and GGT. These enzymes are sensitive markers of liver damage that is caused by the MSG-induced oxidative stress.

In the current study, it has been shown that the livers of MSG-exposed rats exhibited excess mononuclear inflammatory infiltrate around a congested branch of portal vein, and negative Bcl2 immunostaining. These findings were in line with Farombi and Onyema [10] and Khayal et al. [22], who found that MSG-rat liver had marked vacuolation of hepatocytes with pyknotic nuclei and proliferation of bile ducts with lymphocytic infiltration; the sinusoidal spaces showed congestion with numerous Kupffer cells, central vein dilatation and congestion were detected.

Farombi and Onyema [10] and Thomas et al. [25] found that the hepatotoxic effects of MSG were mainly caused by production of ROS, inducing oxidative stress, which led to changes in membrane properties with leakage of the enzymes from the liver cells.

The pathologically high levels of glutamate can cause excitotoxicity by allowing high levels of Ca2+ to enter the cell, which activates a number of enzymes, including phospholipases, endonucleases, and protease enzymes [26]. These enzymes go on to damage cell structures [27]. Apoptotic proteins that target mitochondria may cause mitochondrial swelling through the formation of membrane pores, or they may increase the permeability of the mitochondrial membrane and cause apoptotic effectors to leak out. Mitochondrial proteins are released into the cytosol following an increase in permeability. They bind to inhibitor of apoptosis proteins and deactivate them, preventing them from arresting the apoptotic process and, therefore, allowing apoptosis to proceed. Bcl2 proteins are able to promote or inhibit apoptosis by direct action on mitochondrial permeability, where Bax and/or Bak increase mitochondrial permeability, while Bcl2 and Bcl-xL inhibit it [28].

Our data showed that pretreatment of MSG rats with diltiazem resulted in improvement of the liver functions, with amelioration of structural damage and apoptosis, when compared with rats in G group. These beneficial effects of diltiazem were in agreement with the results of Bojanic et al. [4],[5], who reported that diltiazem prevented the toxic effects of MSG on the hypothalamus and on the ovary in rats when administered during the neonatal period [29].

MSG might have exerted these effects through increasing the permeability of cell membrane for calcium ions. Diltiazem reduces the permeability of calcium ions through the cell membrane and decreasing the intracellular load of calcium and thus preventing the cell changes induced by the MSG. Pretreatment with diltiazem has prevented the development of morphological disorders of testes as Vladmila et al.[30] suggested that calcium overloading may play an important role among the mechanisms of MSG testicular toxicity.

Pretreatment of MSG rats with quercetin led to amelioration of the liver dysfunction, with less structural damage and apoptosis than G group, these effects may be due to the antioxidant effect of quercetin. These findings were in agreement with Farombi and Onyema [10], who reported that treatment with quercetin reduced the increase in MDA induced by MSG administration, and so, reduced lipid peroxidation. The decreased glutathione GSH level elicited by MSG in liver corresponded with marked increase in the activity of glutathione-S-transferase (GST). Khayal et al. [22] reported that administration of quercetin with MSG produced improvement of serum GGT, ALT, and hepatic MDA and GPx. These biochemical changes are also associated with improvement in the histopathological changes in hepatic tissues.

In concomitant pretreatment of MSG-administered rats with diltiazem and quercetin, ALT, AST, GGT, and MDA were reduced, when compared with G, DG, and QG groups, while hepatic tissue GPx and SOD activities were higher, denoting significant improvement in hepatic parameters and oxidative stress. Hematoxylin and eosin staining and Bcl2 immunohistochemical staining of rat liver tissue of DQG group showed reduced structural damage and apoptosis, when compared with G, DG, and QG groups.

The better beneficial effect of the combined pretreatment of the MSG-administered rats with both diltiazem and quercetin than rats in DG and QG groups could be explained an additive effect, as diltiazem seems to act mainly by its anti-inflammatory and antiapoptotic effects, while quercetin acts mainly by its antioxidant effect.


  Conclusion Top


The prophylactic treatment of the MSG-administered rats with diltiazem, quercetin, or both improves the associated hepatic dysfunction by their anti-inflammatory, antioxidant, and antiapoptotic effects. The combined treatment of diltiazem plus quercetin affords higher protection than each treatment did alone, possibly by an additive effect based on their different mechanisms of action.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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    Tables

  [Table 1], [Table 2], [Table 3]



 

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