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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 10  |  Issue : 3  |  Page : 90-97

Anti-ulcer potentials of aqueous extract of Triticum aestivum on delayed healing of experimentally induced/gastric ulcer


1 Department of Human Physiology, Faculty of Basic Medical Sciences, Baze University, Abuja, Nigeria
2 Department of Human Physiology, Faculty of Basic Medical Sciences, College of Medicine, Bingham University, New Karu, Nigeria
3 Department of Physiology, School of Basic Medical Sciences, College of Medicine, Federal University of Technology Akure, Akure, Nigeria
4 Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Nigeria
5 Department of Biochemistry, Phytomedicine, Molecular Toxicology and Computational Biochemistry Research Cluster, Landmark University, Omu-Aran, Nigeria

Date of Submission21-Sep-2022
Date of Decision10-Oct-2022
Date of Acceptance18-Oct-2022
Date of Web Publication05-Dec-2022

Correspondence Address:
Dr. Grace Iyabo Adebayo-Gege
Department of Physiology, Gastrointestinal Tract Inflammation and Neuroscience Unit, Faculty of Basic Medical Sciences, College of Medicine and Health Sciences, Baze University, Abuja
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njecp.njecp_13_22

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  Abstract 

Background: Ulcer reoccurrence and delay of healing caused by certain factors is now a major problem with the treatment of peptic ulcer. This study sought to unravel the role of Triticum aestivum in delayed ulcer healing in Wistar rats. Materials and Methods: Twenty five (25) Experimental animals (male Wistar rats) weighing 120g – 150g were randomly divided into five groups (N = 5) viz; I (Control), II (20% acetic acid ulceration + 2 mg/kg of indomethacin), III, IV, and V received 50 mg/kg, 100 mg/kg and 200 mg/kg of T. aestivum + 20% acetic acid ulceration + 2 mg/kg of indomethacin. Ulcer was induced by serosa application of 20% acetic acid and was delayed by subcutaneous administration of 2 mg/kg of indomethacin for 14 days. Results: Findings from this study showed that the relative body weight changes decreased substantially in delayed untreated group juxtaposed to control which was improved in T. aestivum extract (TAE) groups. Total gastric acidity, ulcer area, and relative stomach weight were substantially (P < 0.05) increased in delayed ulcer group juxtaposed to control group. These changes were substantially reversed in TAE-treated groups. A substantial decrease was observed in the catalase level and expression of nitric oxide accompanied by an increase in malondialdehyde was noted in delayed ulcer group juxtaposed to control which were ameliorated in all TAE treated groups. Histological and macroscopic evaluations revealed that there was a substantial decrease in inflammation and erosion of the gastric mucosa in groups treated with T. aestivum juxtaposed to delayed ulcer group. Conclusion: It can thus be said that aqueous extract of T. aestivum attenuates delayed gastric ulcer healing due to antioxidants and anti-inflammatory properties. The highest concentration (200 mg/kg) in this proved to be the most beneficial.

Keywords: Antioxidants, delayed gastric ulcer, inflammation, nitric oxide, Triticum aestivum


How to cite this article:
Adebayo-Gege GI, Adetomiwa DA, Omayone TP, Akintayo OC, Ozegbe QB, Dimeji IY, Ojo OA. Anti-ulcer potentials of aqueous extract of Triticum aestivum on delayed healing of experimentally induced/gastric ulcer. Niger J Exp Clin Biosci 2022;10:90-7

How to cite this URL:
Adebayo-Gege GI, Adetomiwa DA, Omayone TP, Akintayo OC, Ozegbe QB, Dimeji IY, Ojo OA. Anti-ulcer potentials of aqueous extract of Triticum aestivum on delayed healing of experimentally induced/gastric ulcer. Niger J Exp Clin Biosci [serial online] 2022 [cited 2023 Feb 9];10:90-7. Available from: https://www.njecbonline.org/text.asp?2022/10/3/90/362647


  Introduction Top


Peptic ulcer is a major disorder of alimentary tract that is characterized by the formation of sores and erosions both in the stomach and in the duodenum linings.[1] It is formed as a result of the corrosive action of pepsin and Hydrochloric acid (HCL), stress, Helicobacter pylori ischemia, nonsteroidal anti-inflammatory drugs (NSAIDs), or alcohol consumption leading to severe erosion and necrosis of the mucosa of the upper gastrointestinal tract.[2],[3]

Ulcer healing is a cell-programmed repair event that involves inflammation and resolution of inflammatory responses; it involves cells such as inflammatory cells, platelets, epithelial cells, and fibroblasts.[4] These cells have potential of producing nitric oxide (NO) which is important in the stages of healing.[4],[5] The major problem of peptic ulcer is its delay in healing or recurrence usually referred to as delayed peptic ulcer.[6] This is caused by physiologic or physical stress as well as the use of both steroidal and NSAIDS.[7] Ulcers can also be caused or worsened by drugs such as aspirin, ibuprofen, and other NSAIDs. Due to the lack of side effects relative to the synthetic drugs, approximately 60% of the entire world's population relies almost entirely on herbs and herbal products have long been recognized as an essential source of therapeutically effective medicines.[8]

Wheat (Triticum aestivum) is an annual cereal grain, considered one of the oldest cultivated crops, as a dietary food of ancient civilizations. It is also, an essential diet constituent of working-class individuals before the commencement of the 20th century. The medicinal benefits and health aspects of wheat foods are in several countries.[9] Wheat is very nutritious cereal grain that supplies eaters with many bioactive compounds that are of therapeutic significance. Experimental studies have demonstrated that consumption of whole grains, such as wheat, has been linked to protection against metabolic disorders, cardiovascular risk and cancer.[10] Whole grains are also important as dietary sources of fat-soluble, water-soluble, and antioxidants (insoluble). Recent human nutrition studies indicate encouraging health benefits associated with increased consumption of barley as illustrated by[11] which contains many nutrients, including dietary fiber, antioxidants, Vitamins, minerals (calcium, magnesium, potassium, phosphorus), sphingolipids and unsaturated fatty acid.[12] Indomethacin which is an analgesic, is a popular drug used by patients with arthritis to cause a relief from pain.

Its use as well as other NSAIDS has been reported to cause gastric ulcer and also delay the healing process of the gastric ulcer.[13] Therefore, this study investigates the effect of aqueous extract of T. aestivum on acetic-induced ulceration with the healing process delayed by indomethacin administration in order to mimic unhealed ulcer in humans.


  Materials and Methods Top


Collection of plant materials and extraction from wheat grains

The seeds of T. aestivum (Wheat) was obtained from Medicinal Plant Research and Traditional Medicine Department, National Institute for Pharmaceutical Research and Development, Idu-Abuja. The fresh seeds of T. aestivum (Wheat) were air-dried and grinded into powder using a blender. 500 g of the powdered seeds were macerated in 5 L of distilled water for 48 h with continuous shaking by orbital shaker maintained at 3000 rpm. The solution obtained were then filtered, and vaporized to give an aqueous extract.

Plants' acute toxicity

The acute toxicity (LD50) of aqueous extract of T. aestivum was tested as described by Shah et al. (1997)[14] and Burger et al. (2005)[15] Thirty-five albino rats were divided into seven groups of five rats each (120–150 g).

Before administering the extract, the rats were fasted for 24 h (only drinking water). The extract was mixed with distilled water and given orally in doses of 50,100, 200, 400, 800, 1600, 3200, and 6400 mg/kg body weight.

The seventh group served as the control group and only received distilled water. The rats were monitored for signs of toxicity and mortality for the first critical 4 h, then every hour for the next 12 h, followed by 6 hourly intervals for the next 56 h, for a total of 72 h, and then daily for 7 days.

Experimental animals

Twenty–five (25) male Wistar rats (Albino) (n=5) with a weight range of 120–150 g were employed for this study. They were kept in the rodents' house, College of Health Sciences, Bingham University, Karu and were sheltered under standard conditions of temperature (23°C ± 2°C); humidity (55% ± 15%) and 12 h light (7.00 am–7.00 pm). The care and use of the animals and the experimental design of this study followed the Experimental Animal Care and Use Regulation of Bingham University, Nigeria.

Experimental groups and treatments

The experiment lasted for a period of 14 days with five rats per each group as follows: Group I served as the control and was treated with distilled water; Group II was treated with acetic acid + 2 mg/kg indomethacin. Group III was treated with acetic acid + 2 mg/kg Indomethacin + 50 mg/kg T. aestivum extract (TAE). Group IV received acetic acid + treatment with 100 mg/kg TAE. + 2 mg/kg indomethacin. (Group V was treated with acetic acid + 2 mg/kg indomethacin + 200 mg/kg TAE).

Acetic acid-induced ulceration

Delayed/Unhealed gastric ulcers” were produced by slightly modifying the method of.[16] Briefly, animals were deprived of food but had free access to water 24 h before ulcer induction. Acute gastric ulcer produced by injection of 20% acetic acid (0.04 ml) into the sub serosal layer in the glandular part of the anterior stomach wall to induce ulcer.[17] The acetic acid was removed using a 1 ml syringe and the serosa of the stomach was washed gently with normal saline and returned into the abdominal cavity under ketamine (60 mg/kg) and xylazine(5 mg/kg) anesthesia. The abdomen was then sutured back and the animals were placed in their cages for recovery with free access to air and water. 2 mg/kg of indomethacin was administered to the animals after 5 days to delay the ulcer formed by acetic acid.[18] The animals were sacrificed on 7 days after ulcer induction and gastric lesions evaluated by examination of the inner gastric surface with a dissecting magnifying glass. The diameter (mm2) of the ulcer area was determined by planimetry by two independent observers.

Assay of hematological indices

Blood was collected from the animals via after the administration of both test and standard drugs into a lithium heparinized bottles after 14 days treatment via cardiac puncture. Hemoglobin, red blood cell (RBC), packed cell volume, white blood cell were evaluated using hemocytometry.

Relative organ weight

The relative weight of the stomach of the rats was assessed on 14th day of treatment. All surviving rats were given anesthesia prior to dissection and the absolute weight of the stomach was recorded. The equation below was used to determine the relative weight of the stomach:



Measurement of ulcer area

The depth of ulceration was assessed macroscopically in accordance with the method of.[17] The ulcerated area was reported in mm2.

Total gastric acidity measurement

The acidity of each sample collected was assay by closing the esophageal end and duodenal end of the stomach and then injected with 1 ml. The gastric content was collected into a beaker with 3 ml of normal saline then titrated against 0.01N sodium hydroxide. A drop of phenolphthalein was used as an indicator. After gastric acidity studies, the stomachs were collected for histological and biochemical studies.



Biochemical assay

The animals were sacrificed on the 14th day, the stomach tissue was removed and rinsed to remove debris and homogenized in phosphate buffer at pH 7.4 and thereafter centrifuged. The supernatant of homogenates was employed to estimate protein level,[19] lipid peroxidation (MDA content[20], catalase[21], nitric oxide (NO content).[22]

Histological procedure

The small section of the gastric tissue was cut and placed in 10% formalin before it was taken for histology. The tissue was dewaxed in xylene for 10 minutes before being washed in absolute alcohol (six slow dips). It was then passed through low grades of alcohol, i.e., 80%, 70%, and 50% (six slow dips in each) before being rinsed in water. It was then stained with Harris haematoxylin for 5 minutes before being washed in water. After quickly deffrentiating the tissue in 1% acid alcohol, it was rinsed and blue under tap water for 10 minutes before being counterstain in 1% aqueous eosin for 3 minutes and rinsed in water. It is then dehydrated in escalating alcohol grades (70%, 80%, 90%, and absolute), clear in xylene, and mounted with dpx mountant. The nuclei were blue-purple, while the cytoplasm was pink.

Data analysis

Data were expressed as Mean ± SEM. One-way ANOVA was used to analyze the differences among them followed by Tukey post-hoc test. The statistical difference was taken to be substantial at P < 0.05.


  Results Top


Acute toxicity of Aqueous extract of Triticum Aestivum

Aqueous extract of Triticum Aestivum at different doses to the animals revealed no substantial behavioural changes such as weakness and sluggishness in the animals, nor mortality. Therefore, oral LD50 was not determined because mortality was not observed.

Effect of aqueous extract of Triticum aestivum on Absolute body changes and relative stomach weight

A substantial decrease in absolute body changes was observed in Group II juxtaposed to control which was substantially improved by the administration of TAE. [Figure 1] The relative stomach weight was substantially increased (P < 0.0001) in Group II juxtaposed to control group. All TAE treated Groups (III-V) substantially decreased (P < 0.05) juxtaposed to delayed ulcer Group (II) as shown in [Figure 2].
Figure 1: Effect of aqueous extract of Triticum aestivum on absolute weight changes after ulcer induction in experimental models. **Substantial as juxtaposed with group I. ##Substantial as juxtaposed with group II

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Figure 2: Effect of aqueous extract of Triticum aestivum on relative stomach weight changes during ulcer healing. All values are expressed as mean ± SEM, p < 0.05. ****Substantial as juxtaposed with group I. #### Substantial as juxtaposed with group II. ***# Substantial as juxtaposed with group III

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Effect of aqueous extract of Triticum aestivum on ulcer area, gross morphology and histomorphometry

The administration of acetic acid and thereafter indomethacin resulted in severe ulceration of gastric mucosa in [Plate I] and infiltration of inflammatory cells (gross and histology pictures) leading to substantial increase (P < 0.01) in Group II juxtaposed to control group showing intact gastric mucosa. TAE (50, 100 and 200 mg/kg) showed a substantial decrease in ulcer score in a dose dependent manner juxtaposed to Group II. Group V (200 mg/kg) showed intact epithelium and very mild infiltration of inflammatory cells, while Groups (III and IV) showed mild erosion of gastric epithelium and mild infiltration of inflammatory cells as shown in [Plate II]. The ulcer area is as shown in [Table 1].
Table 1: Effect of Triticum aestivum on the ulcer area

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Effect of aqueous extract of Triticum aestivum on total gastric acidity, malondialdehyde, catalase activity and nitric oxide

The results of Gastric acidity [Figure 3] and MDA [Figure 4] showed a substantial increase in Group II (delayed ulcer) juxtaposed to control Group (I). These effects were reversed by administration of TAE 50, 100 and 200 mg/kg (Groups III-V respectively). Catalase (CAT) [Figure 5] and NO [Figure 6] were substantially decreased by acetic acid and indomethacin administration (Group II). Administration of TAE 50, 100 and 200 mg/kg (Groups III-V respectively) substantially (P < 0.01) increased both CAT and NO juxtaposed to group II.
Figure 3: Effect of aqueous extract of Triticum aestivum on Total gastric acidity in experimental models during ulcer healing. All values are expressed as mean ± SEM. **Substantial as juxtaposed with group I. ##Substantial as juxtaposed with group II

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Figure 4: Effect of aqueous extract of Triticum aestivum on MDA in experimental models. All values are expressed as mean ± SEM. **Substantial as juxtaposed with group I. ##Substantial as juxtaposed with group II

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Figure 5: Effect of aqueous extract of Triticum aestivum on Catalase in experimental models during ulcer healing. All values are expressed as mean ± SEM. **Substantial as juxtaposed with group I. ##Substantial as juxtaposed with group II

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Figure 6: Effect of Triticum aestivum on Nitric Oxide (NO) during ulcer healing in experimental models. All values are expressed as mean ± SEM. **Substantial as juxtaposed with group I. ##Substantial as juxtaposed with group II. *#Substantial as juxtaposed with group III

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  Discussion Top


Peptic ulcer still remains a major gastrointestinal disease especially with the problem of spontaneous relapse and reoccurrence.[17] The reoccurrence could be as a result of the action of certain factors and agents which on their own can cause ulcer such as stress, NSAIDs (indomethacin), hence, delaying the process of healing. The use of acetic acid for gastric ulcer induction and thereafter administration of indomethacin greatly mimic this form of ulcer relapse and reoccurrence.[17] In this study, the acetic acid-induced ulcer model was used which is the best model similar to human ulcer for the study of ulcer healing process.[19] The administration of indomethacin is to either delay the healing process or caused a reoccurrence by its ability to inhibit cyclooxygenase (COX1 and COX2) enzymes.[23] Inhibition of COX results in suppression of several prostaglandin-mediated protective functions such as mucosal defense, maintenance of microcirculation, and modulation of the immune system. Inhibition of COX1 results in decreased mucosal blood flow, alongside decrease mucus and bicarbonate secretion. On the other hand, COX2 inhibition results in loss of vasodilation, delayed wound healing, and increased reactive oxygen species (ROS).[24] The major mechanism of indomethacin in delayed ulceration is probably by inhibition of COX which has two isoforms COX-1 and COX-2.[25] The inhibition of COX leads to decreased production of prostaglandin, which is responsible for maintaining gastric mucosal integrity at baseline, enhance mucus production and potentiate ulcer healing by triggering the cell proliferation, promotion of angiogenesis and restoration of mucosal integrity.[26] Peptic ulceration is mostly characterized by anemia, presence of few RBCs and low hemoglobin in the blood.[27]

Findings from the study shows that indomethacin caused delayed of acetic acid induced gastric count lipid peroxidation, and reducing protein level, CAT and NO and this was reversed by aqueous extract of T. aestivum. The exploration of natural products and medicinal plants extracts has become the most interesting and attractive sources of new therapy for various gastrointestinal disorders, especially in the treatment of peptic ulcers in various experimental models for evaluating anti-ulcer drugs.[28]

In this study, there was substantial increase in the weight changes in the T. aestivum treated Groups (III-IV) juxtaposed to the untreated Group (II). This could be attributed to the nutritious potential of the aqueous extract of T. aestivum. In addition, there was marked decrease in the relative weight of the stomach of the treated group. This corresponds with the values obtained from microscopic score and histological evaluation were T. aestivum was seen to decrease the inflammatory cells infiltration into the stomach.[27] The infiltration of inflammatory cells results in edema as well as inflammation thereby increasing organ weight.[27] Suppression of gastric acidity has long been known to be a major requirement for healing in an injured stomach.[29],[30] Results obtained in this study shows that T. aestivum also has the ability to suppress acid secretion by decreasing gastric acidity value as against what was observed in the delayed ulcer group. A major effect in the administration of NSAIDs is the generation of ROS and inhibiting cell proliferation.[31],[32],[33] Free radicals prevent activities of antioxidant enzymes and start the process of lipid peroxidation which is an important event in the toxicity mechanism of indomethacin.[34] Indomethacin has been reported to lowered antioxidant enzymes (SOD, CAT) activity in rat stomach ultimately inducing gastric ulceration.[35] This coincides with the report by Khan et al.[36] stated that indomethacin administration significantly reduced SOD and catalase activities in nearly all tissues The decrease in antioxidant enzyme activities was linked to significantly increased Lipid peroxidation (LPO) as measured by Malondialdehyde (MDA). It was observed that indomethacin disrupted the antioxidant defense system in the renal cortex and medulla, as well as the small intestine and liver, as evidenced by increased LPO (indicator of tissue injury) and suppressed activity of SOD and catalase in the aforementioned tissues.

According to the experiment carried out by Yoshikawa et al.,[31] indomethacin is said to have caused gastric haemorrhagic erosions and increased TBA-reactive substances in the gastric mucosa, both of which are indicators of lipid peroxidation. This was linked with the ability of indomethacin to also increase leucocyte adherences, that could enhances the presence of lipid peroxidation products and at same time cause depletion of the protective scavengers.

Malondialdehyde (MDA) is an active aldehyde derived from the action of ROS in the body, its level is indicative of the existence of oxidative stress.[37] MDA level was grossly increased in the delayed ulcer untreated group juxtaposed with other treatment groups. The observed reduction in MDA level in the T. aestivum treated groups is an indication that T. aestivum possesses antioxidative properties. It could also be that T. aestivum is able to enhance the production of antioxidant as observed by the increase CAT activities in all T. aestivum treated groups compare to delayed ulcer group. Previous studies have also shown the antioxidant effect of T. aestivum[38],[39] and are in line with our study. NO plays a multiple role in both intracellular and extracellular signaling mechanism with implication for health and disease, it has been postulated that its actions may be therapeutically valuable in diseases. Research has shown it is an important substance needed for angiogenesis during ulcer healing process. NO is also known to be a potent vasodilator to blood vessel which prevents platelets and leukocytes adhesion in microvasculature as well as micro ischemic conditions.[40] The level of NO was elevated in the T. aestivum treated juxtaposed with the ulcerated untreated group. Generally, the protection produced by the aqueous extracts of T. aestivum against acetic acid-induced gastric ulceration may not be unconnected to its beneficial medicinal characteristics occasioned by phyto-metabolite constituents. These include ability to scavenge free radicals and regulate mucosal membrane permeability thereby countering the effect of indomethacin on gastric acid secretion. This is in agreement with the submissions of[41],[42] where gastro-protective potentials of plant extracts against indomethacin-ulcerated rats were associated with their polyphenolic compounds. Results of this study showed that animals treated with aqueous extract of T. aestivum showed low lesion in stomach juxtaposed to unhealed ulcerated animals. These increase in CAT and NO and decrease in MDA, probably enhanced vasodilation and reduces adherence of both platelets and leucocytes within the endothelial cell micro vascular beds. This synergetic cascade might have helped in mitigating against the adverse effect of indomethacin treatment thus increasing the protective mucosal defense and possibly angiogenesis.


  Conclusion Top


In general, the attenuation of gastric affronts of acetic acid and indomethacin by administration of aqueous extract of T. aestivum regimen is indicative for their excellent gastro-protective and anti-oxidative potentials in rats. Efforts are currently ongoing to investigate the exact anti-ulcerogenic principle(s) in these extracts, and also identify their possible synergistic potentials against gastric ulcer. These observations were further buttressed by histological results which revealed the healing effect of T. aestivum on gastric ulcers.

Acknowledgment

We appreciate the technical staff of department of human Physiology, Faculty of Basic Medical Sciences.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
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