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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 34  |  Issue : 3  |  Page : 1048-1053

Therapeutic effect of sodium 2-mercaptoethanesulfonate on dextran sulfate sodium-induced ulcerative colitis in rats


1 Department of Clinical Pharmacology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission19-Nov-2019
Date of Decision11-Dec-2019
Date of Acceptance15-Dec-2019
Date of Web Publication18-Oct-2021

Correspondence Address:
Samah M Wadan
El-Bagour, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_340_19

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  Abstract 


Objective
The aim of the study was to investigate the possible therapeutic effects of sodium 2-mercaptoethanesulfonate (MESNA) on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in rats.
Background
Incidence of UC is high worldwide and has started to increase more and more specifically in the middle-east in the past few years. The established treatment of UC is still unsatisfactory, so the authors seek to develop new therapeutic modalities for UC.
Materials and methods
A total of 40 adult rats were divided into five groups (n = 8). Group 1 (control) is vehicle-treated group. Group 2 (DSStreated) received DSS 5% in drinking water for 7 days. Group 3 (DSS–Mesna-treated) received DSS 5% in drinking water for 7 days followed by Mesna 400 mg/kg/day intraperitoneal for 10 days. Group 4 (DSS–sulfasalazine-treated) received DSS 5% in drinking water followed by sulfasalazine (100 mg/kg/day; orally for 10 days). Group 5 (DSSMesna and sulfasalazine treated) received DSS 5% for 7 days followed by combined drugs for 10 days. Colonic tissue was used for estimation of reduced glutathione and superoxide dismutase. In addition, histopathological changes of rat colon were assessed.
Results
Mesna, sulfasalazine, and their combination significantly reduced body weight loss. They significantly increased the antioxidant defense (superoxide dismutase and reduced glutathione). They improved histopathological changes of UC.
Conclusion
Mesna may play a role in treatment of DSS-induced UC. Its combination with sulfasalazine showed better therapeutic effect than Mesna used alone.

Keywords: dextran sulfate sodium, oxidative stress, sodium 2-mercaptoethanesulfonate, sulfasalazine, ulcerative colitis


How to cite this article:
ELbatsh MM, ELhenawy EEM, Samaka RM, Wadan SM. Therapeutic effect of sodium 2-mercaptoethanesulfonate on dextran sulfate sodium-induced ulcerative colitis in rats. Menoufia Med J 2021;34:1048-53

How to cite this URL:
ELbatsh MM, ELhenawy EEM, Samaka RM, Wadan SM. Therapeutic effect of sodium 2-mercaptoethanesulfonate on dextran sulfate sodium-induced ulcerative colitis in rats. Menoufia Med J [serial online] 2021 [cited 2024 Mar 29];34:1048-53. Available from: http://www.mmj.eg.net/text.asp?2021/34/3/1048/328332




  Introduction Top


Ulcerative colitis (UC) is considered a public health problem worldwide [1]. In 2015, 1.3% of US adults (three million) reported being diagnosed with inflammatory bowel disease (either Chron's disease or UC) [2]. This was considered a large increase from 1999 (0.9% or two million adults) [3]. Its precise etiology is still unknown, but it is believed to arise of dysfunctional immune response [4]. UC is considered a multifactorial disease that results from combined genetic, environmental, immunological, and infective factors [5]. The pathogenesis of UC is not well understood, but many studies suggest that oxidative stress is involved in the development of the disease as intestinal inflammation is associated with increased production of reactive oxygen species (ROS) [6]. One of the most important inflammatory cytokines in the pathophysiology of UC is tumor necrosis factor-α, which attract macrophages leading to increased pro-inflammatory cytokines and chemokines, affect endothelial cells adhesion molecules leading to increase cell infiltration, and increase ion transport and cell permeability, leading to compromised barrier function [7],[8].

UC animal models are useful tools in understanding pathophysiological, histopathological, and biochemical processes occurring in UC and in the development of new therapeutic agents.

Dextran sulfate sodium (DSS) model of UC is one of the most common models of UC. DSS is a polyanionic derivative of dextran with a chemical formula of (C6H7Na3O14S3) n. It is directly toxic to colonic epithelium with direct injury to epithelial cell barrier and entry of luminal organism into lamina propria leading to stimulation of immune system with increasing production of pro-inflammatory cytokines, cells with cytotoxic potential, and ROS [9],[10].

Sulfasalazine is 5-aminosalisylic acid (5-ASA) derivative. 5-ASA is the active component of sulfasalazine. Its mechanism of action is unknown; however, it is thought to modulate local chemical mediators of inflammatory response, especially leukotrienes and considered to be free radical scavenger [11].

Sodium 2-mercaptoethanesulfonate (Mesna) is used clinically as a chemoprotective agent by supplying sulfhydryl group, which neutralizes acrolein, an urotoxic metabolite of cyclophosphamide [12]. Mesna has well-defined antioxidant, anti-inflammatory, and antiapoptotic action [12]. It was found that Mesna can neutralize ROS by its sulfhydryl group and can reduce inflammatory mediators [12].

Therefore, this study aimed to assess the potential therapeutic effect of Mesna and its combination with sulfasalazine on DSS-induced UC in rats.


  Materials and method Top


A total of 40 adult male albino rats weighting 120–200 g were purchased from a local vendor. Animals were acclimatized to the laboratory conditions for 1 week before starting the experiments. Animals were housed in cages under controlled conditions: average temperature of 25 ± 2°C, relative humidity about 50%, and 12 h light/dark cycles during the experiment. Standard water and food were allowed. All experiments were carried out in accordance with protocols approved by the local experimental Ethics Committee for Animal Research in Faculty of Medicine, Menoufia University, and complied with the Guide for the Care and Use of Laboratory Animals (ILAR 1996).

Rats were divided into five groups (n = 8): first, control group, which is vehicle-treated group; second, DSS-treated group, which received 5% DSS salt (MW 36000–50000 kDa) (Sigma Aldrich, St Louis, Missouri, USA) dissolved in drinking water for 7 days [13]; third, DSS-Mesna treated group, which received DSS for 7 days as in group 2 followed by Mesna (Uromitexan; Baxter Oncology Gmbh, Halle/Westfalen, Germany) at a dose of 400 mg/kg/day intraperitoneal for 10 successive days [14]; fourth, DSS-sulfasalazine-treated group, which received DSS as in group 2 followed by sulfasalazine (Sigma-Aldrich) at a dose of 100 mg/kg/day orally through orogastric tube for 10 successive days [15]; and fifth, combination group, which received DSS 5% for 7 days followed by Mesna at a dose of 400 mg/kg/day intraperitoneal and sulfasalazine at a dose of 100 mg/kg oral for 10 successive days. Body weight of animals was measured at the start, eighth day, and at the end of the study.

Animals were killed by cervical dislocation 24 h after the last treatment. The abdominal cavity was rapidly opened, and the entire colons were removed. Part of the colon was homogenized in 5–10 ml cold phosphate buffer (pH 7.2, 50 mol/l) per gram tissue. Homogenate (10% W/V) was centrifuged at 4000 rpm for 15 min at 4°C, and the supernatant was collected, and frozen at −20°C until used for determination of superoxide dismutase (SOD) activities and reduced glutathione (GSH) with kits from Biodiagnostic Company, Egypt.

The other part of the colon was preserved and fixed for 24 h in 10% neutral buffered formalin. The collected colonic biopsies were sent to Pathology Department, Faculty of Medicine, Menoufia University, for routine processing and preparation of hematoxylin and eosin-stained slides.

Results were collected, tabulated, and statistically analyzed by Statistical Package for the Social Sciences (SPSS) version 24 (SPSS Inc., Chicago, Illinois, USA). Results were expressed as mean ± SEM, and percentage.

The statistical significance between the means of different groups was analyzed using one-way analysis of variance followed by Fisher's least significant difference (LSD) tests for parametric data or Kruskal–Wallis test for nonparametric data. Level of statistical significance was set at P less than 0.05.


  Results Top


Mesna, sulfasalazine, and their combination improved body weight of DSS-induced UC animals. The most significant improvement is in the combination-treated group.

The healthy control rats gained weight as expected during the experimental period, whereas the other four groups which received DSS showed significant decrease in body weight, which was measured after induction, as compared with the control group (P < 0.001). At the end of experiment, DSS-treated group (diseased group) showed continuous steady decrease in body weight (115.62 ± 3.74 for DSS-treated group vs 188.12 ± 3.80 for control group), with P less than 0.0001. However, treated groups showed significant decrease in body weight loss, and in some animals, weight started to increase toward normal values (128.78 ± 4.19 for Mesna-treated group vs 115.62 ± 3.74 for DSS-treated group, 127.13 ± 3.70 for sulfasalazine-treated group vs 115.62 ± 3.74 for DSS-treated group, and 139.55 ± 2.85 for combination-treated group vs. 115.62 ± 3.74 for DSS-treated group, with P < 0.001 for all). There was no significant difference in body weight between Mesna-treated group and sulfasalazine-treated group, with P = 0.754. On the contrary, there was a significant difference in body weight of combination-treated group when compared with Mesna-treated group or sulfasalazine-treated group, with P = 0.046 and. 023, respectively.

Mesna, sulfasalazine, and their combination mend the oxidative stress produced by DSS by increasing level of GSH and SOD. The most significant improvement was in the combination-treated group. Tissue level of GSH (nmol/g) of DSS-treated group significantly decreased compared with the control group (35.87 ± 0.440 vs 80.0 ± 0.707, P < 0.0001). Tissue level of GSH of Mesna-treated group significantly increased compared with the DSS-treated group (68.5 ± 0.42 vs 35.87 ± 0.440, P < 0.0001). Tissue level of GSH of sulfasalazine-treated group was significantly increased compared with the DSS-treated group (69.62 ± 59 vs 35.87 ± 0.440, P < 0.0001). Tissue level of GSH of combination-treated group was significantly increased compared with DSS-treated group (76.37 ± 0.595 vs 35.87 ± 0.440, P < 0.0001). There was no significant difference between tissue level of GSH in sulfasalazine-treated group compared with Mesna-treated group (69.62 ± 59 vs 68.5 ± 0.42, P = 0.166). On the contrary, tissue level of GSH was significantly increased in combination group than Mesna-treated group and sulfasalazine-treated group (76.37 ± 0.595 vs 68.5 ± 0.42 and 69.62 ± 59; P < 0.001 and < 0.0001, respectively) [Table 1].
Table 1: Effect of Mesna and/or sulfasalazine on body weight, tissue glutathione, and tissue superoxide dismutase

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Tissue level of SOD (unit/g) of DSS-treated group significantly decreased compared with control group (79.37 ± 0.94 vs 157.25 ± 0.67; P < 0.0001). Tissue level of SOD of Mesna-treated group was significantly increased compared with DSS-treated group (144.62 ± 0.86 vs 79.37 ± 0.94; P < 0.0001). Tissue level of SOD of sulfasalazine-treated group was significantly increased compared with DSS-treated group (145.37 ± 1.132 vs 79.37 ± 0.94; P < 0.0001). Tissue level of SOD of combination group was significantly increased compared with DSS-treated group (150.37 ± 0.705 vs 79.37 ± 0.94, P < 0.0001). On the contrary, there was no significant difference between tissue level of SOD in sulfasalazine-treated group compared with Mesna-treated group (145.37 ± 1.132 vs 144.62 ± 0.86; P = 0.551). However, tissue level of SOD was significantly decreased in combination group than-Mesna treated group and sulfasalazine-treated group (150.37 ± 0.705 vs 144.62 ± 0.86 and 145.37 ± 1.132; P < 0.001 and < 0.001, respectively) [Table 1].

Mesna, sulfasalazine, and their combination promote healing of DSS-induced mucosal injury and ameliorate colonic inflammation. Histopathological assessment of colonic tissues of rats in the different groups using the hematoxylin and eosin stain showed that control rats exhibited normal architecture and histology of colonic tissues [Figure 1]a. In DSS group, there was a significant change in the histopathological parameters compared with the control group; there was extensive mucosal ulceration (P < 0.001), gland atrophy (P < 0.01), decreased mucosal mucin (P < 0.01), and massive inflammatory infiltrate, mostly lymphoplasmacytic and eosinophils (P < 0.001) [Figure 1]b, [Figure 1]c, [Figure 1]d and [Table 2]. In Mesna-treated group, there was significant improvement in the histopathological parameters compared with DSS-treated group, as there was focal mucin depletion, superficial healing ulcers, and mild mucosal gland atrophy. Submucosa partially was covered by granulation tissue, mild-to-moderate submucosal edema and mild inflammatory cellular infiltrate [Figure 2]c and [Figure 2]d and [Table 2]. In sulfasalazine-treated group, there was denudation of colonic mucosa and superficial healing ulcers, with no atrophic changes [Figure 2]a and [Figure 2]b and [Table 2]. Co-administration of Mesna and sulfasalazine in DSS-Mesna-sulfasalazine-treated group caused a marked improvement in the histological structure when compared with DSS group, as there was no shedding of mucosa, ulceration, exposure of submucosa, nor mucosal edema. There was very mild gland atrophy and minimal inflammatory infiltrate [Figure 3]a, [Figure 3]b, [Figure 3]c and [Table 2].
Figure 1: Histopathological assessment of colonic tissue of rats of control group and DSS-induced UC group. (a) Section of normal control showed colonic mucosa with unremarkable pathological changes. (b) Section of DSS-induced UC showed massive destruction of colonic wall affecting mainly mucosa and submucosa. (c) Section of DSS-induced UC showed aphthous ulcer (arrow) with lamina propria edema and inflammatory infiltrate. (d) Section of DSS-induced UC showed complete ulceration of mucosa and replacement by diffuse mucosal and submucosal inflammatory infiltrate. Hematoxylin and eosin ×100 for a, b and c and ×200 for d. DSS, dextran sulfate sodium; UC, ulcerative colitis.

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Figure 2: Histopathological assessment of colonic tissue of rats of Mesna-treated group and sulfasalazine-treated group. (a) Section of DSS-sulfasalazine-treated group showed denudation of colonic mucosa and superficial healing ulcers with no atrophic changes. (b) High-power view of previous photograph showed superficial mucosal denudation, reparative changes, and diffuse mild inflammatory cellular infiltrate. (c) Section of DSS-Mesna-treated group showed focal mucosal mucin depletion, mild mucosal gland atrophy, and mild inflammatory cellular infiltration. (d) Section of DSS-Mesna-treated group showed superficial healing aphthous ulcer (black arrow) and fissured ulcer (red arrow) within healing mucosa. Hematoxylin and eosin × 40 for a and d and × 100 for b and c. DSS, dextran sulfate sodium; UC, ulcerative colitis.

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Figure 3: Histopathological assessment of colonic tissue of rats of combination-treated group. (a) Section of combination-treated group showed repair of mucosal pathological changes with very mild atrophy and mild inflammatory infiltrate. (b) Section of combination-treated group showed complete healing of mucosal pathological changes with mild atrophy (red arrow). (c) Another case of combination-treated group showed restoration of normal mucosal architecture. Hematoxylin and eosin × 100 for a and × 40 for b and c. DSS, dextran sulfate sodium; UC, ulcerative colitis.

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Table 2: Effect of Mesna and/or sulfasalazine on histopathological parameters

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  Discussion Top


Incidence of UC is high worldwide and has started to increase more and more specifically in the Middle East in the past few years [1]. Recent data showed there is increase in the disease incidence in the Middle East, which is usually explained by lifestyle changes, such as urbanization, and changes in alimentary habits, such as greater consumption of fast food, greater consumption of carbohydrates, and a lower daily intake of alimentary fibers [16].

Types of drugs that are available for treatment of UC at present are not abundant, and their effects are unsatisfactory; so, we still are in a need to develop new, effective drugs [17].

DSS-induced colitis is one of the most suitable models for testing new drug modalities. This is because it is easy to conduct and produces biochemical and histopathological changes similar to that occurring in humans [18].

Recent studies showed that Mesna could be used as a therapeutic agent for treatment of UC, owing to its antioxidant action [19].

In the present study, DSS administration decreased body weight of animals. This feature resembles the problem of weight loss occurring in patients with UC. This result is in agreement with Chong et al. [20], Shin et al. [21], and Rigaud et al. [22] who stated that this change in body weight could be attributed to progressive reduction in food intake, severe diarrhea, and loss of body fluids. Mesna, sulfasalazine, or their combination minimized weight loss and started to restore normal rate of weight gain. This result is in agreement with Ioannis et al. [14] who explained this improvement by increasing food intake, attenuation of diarrhea, and maintaining body fluids, which is owing to attenuation of histopathological damage and restoration of absorptive surface area.

Administration of DSS leads to marked reduction in GSH and SOD. This is owing to oxidative stress and reduction of antioxidant enzymes. These results are consistent with previous studies [23]. Reduction in GSH may probably result from increased conversion to oxidized glutathione (GSSG), as reported by Asima et al. [24]. The reduction in the antioxidant enzyme (SOD) may be owing to its consumption in the dismutation of O2 which increased in DSS-induced UC into O2 and H2O2, as reported by Nozik et al. [25] and Asima et al. [24]. Treatment with Mesna, sulfasalazine, or their combination has significantly elevated the levels of GSH and SOD. The etiology that Mesna can elevate levels of GSH and SOD can be explained by strong antioxidant and free radical scavenging activity of Mesna. This is owing to its sulfhydryl group, which can neutralize ROS generated by DSS, so it can serve GSH and SOD and prevents their depletion. This is in agreement with Kabasakal et al. [26] and Sener et al. [27]. Sulfasalazine also has a powerful antioxidant action and can neutralize ROS produced by DSS, as stated by Walaa et al. [15].

Treatment with Mesna, sulfasalazine, or their combination has markedly improved the histopathological damage of the colon. This is in agreement with Ioannis et al. [14] who reported that this improvement may be owing to ability of Mesna to increase the inducible nitric oxide synthase (iNOS) and nitric oxide (NO), which increase mucosal blood flow and promote mucosal healing. Sulfasalazine decreases the production of leukotriene's (LTs), prostaglandin E2, and free radicals; inhibits immune responses of immune cells; decreases small vessel inflammation in lamina propria of inflamed parts; increases mucosal blood flow so improve healing; inhibits the activity of natural killer cells and T-cells; and acts on several arachidonic acid metabolism pathways, resulting in a net increase in prostaglandins, which possess both anti-inflammatory and immunosuppressive effects, and a decrease in proinflammatory lipoxygenase. This was mentioned by Simmonds et al. [28].

In the present study, co-administration of Mesna and sulfasalazine has superior effect in treatment of DSS-induced UC than each drug given alone. This could be explained by the antioxidant action of Mesna [12], in addition to the anti-inflammatory, free radical scavenging action, and downregulation of chemical mediators of inflammation of sulfasalazine [11].


  Conclusion Top


In conclusion, Mesna when used alone or in combination with sulfasalazine could be a promising drug for treatment of UC. The therapeutic effect of this drug is best explained by its antioxidant and free radical scavenging activity. Observed data showed that combination of Mesna with sulfasalazine produces more marked effect than each drug used alone. This drug combination may provide a therapeutic advantage for treatment of UC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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