Egyptian Journal of Basic and Clinical Pharmacology
Vol. 11 (2021), Article ID 101541, 8 pages
doi:10.32527/2021/101541
Influence of Low and High Doses of Capsicum Extract on Indomethacin Induced Gastric Ulcer in Rats
Abstract
Background: Capsicum (Caps) has always been used as food spice. Recently, it has shown benefits in peptic ulcer but effective dose range and mechanisms mediating its effect are not known. This work is aimedto evaluate the gastroprotective effect of a wide dose range of Caps, compared with ranitidine (Ran), against indomethacin (Indo)-induced ulcer. Methods: 42 female adult Wistar albino rats were allocated into seven groups: 1) control (Cnt), 2) Indo (25 mg/kg p.o.), groups 3-6 were given Caps at 200, 400, 800 and 1600 mg/kg, p.o. prophylactically for 6 days. The last group was given 100 mg/kg, p.o. Ran for 6 days. Blood samples were withdrawn for analysis of MDA, GSH, NO, and SOD and stomachs were dissected for histopathological examinations and measurement of TNF-α and IL-8. Results: Caps replenished GSH and SOD and reduced TNF-α, IL-8, MDA and NO. It also reduced mucosal focal ulceration, neutrophil infiltration, ulcer index in a dose dependent manner. Importantly, Caps ulcer-protective effects were equivalent to those of 100 mg/kg Ran at 800 and 1600 mg/kg with an ED50% of 350 mg/kg. Conclusion: Caps extract possesses a dose-dependent ulcer-protective effect that is equivalent to that of Ran at relatively high doses.
1. Introduction
Stomach is a sensitive digestive organ that is exposed to several factors capable of causing multiple disorders such as gastritis, gastric ulcers, and gastric cancer. Gastric ulcer is one of the most widespread diseases in the world. It affects nearly 5% of the global population, of whom ∼ 80-90% are also diagnosed with duodenal ulcer [1]. Predominant causes of peptic ulcer worldwide include the rising levels of stress, alcohol consumption, long intake of non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and infection with H. Pylori [2]. Stomach responds to such stressors by enhancing inflammatory and oxidative stress responses.
Gastric inflammation is mediated by various mechanisms implicating several proinflammatory cytokines like interleukin (IL)-1β, IL-2, IL-6, IL-8 and tumor necrosis factor-α (TNF-α) [3]. In addition, the imbalance between free radicals such as reactive oxygen species (ROS) and defensive factors such as superoxide dismutase (SOD) appear to contribute to gastric ulcer generation [4]. Numerous medications, as proton pump inhibitors, H-2 blockers, antacids, and antibiotics are used to treat peptic ulcers. However, recurrence rate of peptic ulcer is relatively high, which has led scientists to focus on natural substances such as honey and red pepper for their potential ulcer-protective effects.
Contrary to the popular belief, red chilli pepper [a.k.a. capsicum (Caps)] has been found to have gastroprotective effect against gastric mucosal injury produced by NSAIDs and ethanol in animals and humans due to the presence of a functional substance called capsaicin [5-7]. The structure of capsaicin (8-methyl-N-vanillyl-6-nonenamide, the active ingredient in cayenne pepper) is similar to that of eugenol, which induces long-lasting local analgesia [8]. Studies have shown that capsaicin exerts different effects on gastric motility and is protective against acetylsalicylic acid-induced gastritis model [9-11]. Literature suggesting an ulcer-promoting effect for capsaicin is also present. Kang et al. 1996 showed that capsaicin promotes acetic acid-induced gastric ulcer potentially through its gastric hyperemic effect [12]. It is worth mentioning that caps extract contains, besides capsaicin, antioxidants like beta carotenes and vitamin C which also have gastroprotective effects against NSAID-induced gastric ulcer [13,14].
Relatively recent studies have shown that capsaicin provides a gastro-protective effect at relatively low doses. However, when used at high levels, desensitization of capsaicin-sensitive afferent nerves occurs, and it eventually loses its gastro-protective effects [15]. In fact, these nerves were found essential for gastro-protection provided by proton pump inhibitors such as lansoprazole and omeprazole [15, 16]. Given the contradicted reports of capsaicin doses, the current study is aimed to explore the effect of different doses of Caps extract (cayenne pepper) on indomethacin (Indo)-induced peptic ulcers in rats and the possible pathways mediating its effect. Caps extract was chosen for our study because it is readily available and consumed by people from different cultures worldwide.
2. Material and Methods
2.1. Materials
Indomethacin, 50 mg ampoules were obtained from NILE Co. for Pharm. & Chemical Ind. Ranitidine (Ran) [Zantac tablets, 150 mg] was purchased from GlaxoSmithKline Industries. Ran tablets were dissolved in distilled water and was administered at a dose 100 mg/kg via an oral gavage tube. Red raw chilli was purchased from a local vegetable market (Cairo, Egypt) and extract was prepared according to Abduljawad et al (2013) [17]. 1 g of the powdered red chilli was mixed with 100 ml distilled water. This mixture was boiled for 10 minutes then left to cool. The liquid was then filtered by a filter paper to remove particulate matter. Thereafter, the filtrate was lyophilized and reconstituted in 1.5 ml distilled water and administered using stomach oral tube.
2.2. Animals
Forty two adult female Wistar Albino rats weighing between 150 to 200 g were purchased from the National Institute of Ophthalmology, Giza, Egypt. Rats were acclimatized and housed in the animal house of October University for Modern Sciences and Arts (MSA), Egypt, under constant conditions (12-hour light/dark cycle, oriental chow pellet and water ad libitum). Rats were allocated randomly into seven groups, n=6 rats/group. Procedures involving animals and their care were approved by the MSA animal ethics committee guidelines and follow EU Directive 2010/63/EU for animal experiments.
2.3. Induction of peptic ulcer by indomethacin
Peptic lesions were induced according to the method reported by Djahanguiri (1969), with few modifications [18]. Modifications include using 25 mg/kg oral dose of indomethacin instead of i.p. 40 mg/kg. Each 1 ml ampoule containing 50 mg Indo was diluted up to 25 ml with distilled water to obtain a solution of 2 mg/ml. Doses of 25 mg/kg were administered p.o. after a fasting period of 12-14 h (with free access to water).
2.4. Experimental design
Animals were divided into seven groups (n=6 each): 1) control (Cnt): received 1 ml saline /100 g p.o., 2) Indo-treated rats as a model of ulcer: received a single oral dose of Indo (25 mg/Kg), 3) Caps-treated rats: received Caps orally at 200, 400, 800, 1600 mg/kg/day for 6 days p.o., 4) Ran-treated rats: received 100 mg/kg Ran daily for 6 days p.o. On the seventh day of the experiment, a single oral dose Indo (25 mg/kg) was administered to Indo-, Caps- and Ran-treated rats after being fasted for 12-14 hours. Rats were then fasted again for 12 h to avoid mixing of gastric contents with Indo dose. Thereafter, blood samples were collected from the jugular vein of all animals, under anesthesia, and rats were euthanized by cervical dislocation. Blood was allowed to stand for 30 minutes at room temperature, then was centrifuged at 4000 rpm for 20 min for separation of serum. Serum was removed and kept at -20ºc until used for the analysis of malonaldehyde (MDA), and reduced glutathione (GSH), nitric oxide (NO), and superoxide dismutase (SOD).
Stomachs were dissected, tied around both openings (cardiac and pyloric sphincters) and injected with 3 ml distilled water. Stomachs were then opened longitudinally, washed with saline, and put on a clean filter paper and examined under dissecting microscope for the determination of gastric ulcer index as previously described by Bhattamisra et al. 2019 [19]. Thereafter, stomachs were cut into two halves. One-half was kept in 10% formaldehyde for histo-pathological examination and the other half was frozen at -20̊ for the analysis of TNF-α and IL-8.
2.5. Histo-pathological Examination
Stomach specimens were collected from rats of all experimental groups at the end of the study in 10% neutral buffered formalin (pH=7.0), dehydrated in ethyl alcohol, then cleared in xylol and embedded in paraffin. The tissue samples were then sectioned at 4-6 microns and stained with heamtoxylin and eosin [20].
2.6. Cytokines and oxidative stress markers assessment
IL-8, GSH, SOD, MDA and TNF-α were determined spectrophotometrically according to the manufacturer's protocol using kits supplied by Bio-diagnosticⓇ, Egypt.
2.7. Statistical Analysis
Graphpad Instat 3.0 was used for statistical analysis. Data is reported as mean ± SE (range). One-way analysis of (ANOVA) followed by Tukey-Kramer test for multiple comparisons were used for comparisons among the groups. The level of significance was set at α < 0.05.
3. Results
3.1. Pro-inflammatory mediators and oxidative stress markers
Indo treatment at 25 mg/kg resulted in 2.6- and 2.8-fold increase in TNF-α and IL-8 levels in the stomachs, respectively. Prior treatment with Caps reduced the production of TNF-α (15-58%) and IL-8 (14-55%) in a dose-dependent manner with reductions being equivalent to those produced by Ran (51% and 50% For TNF-α and IL-8, respectively) at the two highest tested doses (800 and 1600 mg/kg, Fig. 1A). Furthermore, Indo treatment resulted in 86% and 83% reductions in GSH and SOD levels in serum samples isolated from Indo-treated rats. These reductions were alleviated by Caps extract with significant 1.5-5.8-fold and 2-4.5-fold increase in GSH and SOD levels, respectively, in serum samples from rats treated with different doses of Caps. These effects were dose-dependent and the effect of Caps at 800 and 1600 mg/kg dose was comparable to that of 100 mg/kg Ran (Fig. 1B). The lipid peroxidation product, MDA, was significantly increased (2.5-fold) by Indo treatment. However, Caps extract caused significant gradual reductions (12-50%) in MDA levels (Fig. 1C). A dose-dependent decrease (16-52%) in NO was also observed for Caps and the effect was comparable to that of Ran at the two highest tested doses Fig. 1C.
3.2. Histopathological findings
Histopathological assessment of Cnt stomachs showed normal histological structure of mucosa, glands, submucosa and muscularis (Fig. 2A, B and C). Indo, at 25 mg/kg oral dose, showed focal ulcerations and necrosis of the mucosal surface and massive inflammatory cells infiltration (Fig. 2D, E and F). As expected, Ran treatment (100 mg/kg) resulted in an ulcer-protective effect. Stomach samples from Ran-treated rats showed intact mucosa and the focal inflammatory cell infiltration of submucosa was dramatically reduced (Fig. 2G, H and I).
At the lowest dose level (200 mg/kg), Caps did not seem to affect Indo-mediated ulceration. Stomachs of these rats showed desquamation of mucosal lining epithelium with massive inflammatory cells infiltration, oedema in the submucosa and hypertrophy in muscularis (Fig. 3A, B, and C). Likewise, treatment with 400 mg/kg Caps resulted in focal ulceration and necrosis of the mucosa and inflammatory cells infiltration in the lamina propria and submucosa underneath the ulceration (Fig. 3D, E and F). At 800 mg/kg dose of Caps extract, diffusion of inflammatory cells infiltration in mucosa, submucosa, muscularis and serosa was reduced (Fig. 3G, H and I). At 1600 mg/kg dose, Caps ulcer-protective effect was even clearer. Stomachs of these rats showed very mild oedema with less infiltration of inflammatory cells in the submucosal layer and intact mucosa (Fig. 3J, K and L).
Gross evaluation of stomach tissues showed gradual significant reductions in the ulcer index with higher doses of Caps extract (Fig. 4A). Percentage of reductions in ulcer index ranged from 23-95% at the different tested doses of Caps extract. Fitting the observed dose-response data to simple Emax model equation ( ) indicated that a dose of 350 mg/kg of Caps extract provide 50% of the maximum ulcer protection (Fig. 4B).
4. Discussion
Caps is known for its irritant effects however its extract/active component have paradoxically been used topically as analgesics in patients with arthritis and musculoskeletal pain since the 1980's [21]. Caps extract oral supplements are also marketed for weight loss at 500 mg and 1000 mg strength which emphasizes the safety of the whole extract for internal use by humans. Furthermore, phenylcapsaicin, a synthetic chemical, was approved for marketing for that purpose in 2019 in Europe and the United States based on the fact that “it isn't nutritionally disadvantageous” [22]. Research evidence has shown that Capsaicin may be beneficial in the treatment and/or prevention of other disorders such as diabetes, hypertension, stroke, and gastric ulcer [23-26]. In this work we aimed to characterize its gastro-protective effect in vivo using an NSAID-model of gastric ulcer, in comparison with Ran, a widely used anti-ulcer drug. Our results show that prior administration of Caps protected the rats from Indo-induced gastric ulcer in a dose dependent manner. This effect was mainly mediated via the inhibition of Indo-mediated induction of neutrophil infiltration, inflammatory cytokines (TNF- α and IL-8), NO and lipid peroxidation (MDA) and the inhibition of Indo-mediated depletion of GSH and SOD. Importantly, Caps gastric protective effect was comparable to that of a 100 mg/kg Ran at the two highest tested doses (800 and 1600 mg/kg) which underlines its efficacy and safety at these dose levels.
NSAIDs are well known for their gastric ulcer adverse effect especially with chronic use. Therefore, in 2010 the FDA has approved the marketing of VimovoⓇ (a fixed-dose combination of naproxen and esomeprazole) for the control of osteoarthritis and rheumatoid arthritis pain to reduce the ulcer risk in these patients [27]. Despite this, gastric ulcer continues to be the most common adverse effect of this drug product combination, experienced by >5% of patients [27]. We, as well as others, therefore assumed that using natural readily available diets/herbs might protect against NSAID-induced gastritis especially when used on regular basis. Although NSAIDs are historically known to induce gastritis through prostaglandin inhibition, other mechanisms, local and systemic, were also found to contribute to this adverse effect [4].
It is well established that pro-inflammatory mediators such as TNF-α and IL-8 are upregulated following NSAID treatment and are essential molecules in the induction of ulcer [28-30]. TNF-α (via TNF receptor-1) and IL-8 [29] stimulate the recruitment of neutrophils and monocytes by inducing adhesion molecules on the vascular endothelium (ICAM-1) and neutrophils (CD11b ⁄CD18), leading to their activation and subsequent tissue damage. This result in physical occlusion of microvessels and ischemia leading to the release of ROS and proteases [4, 31]. Prior treatment with Caps extract markedly reduced TNF-α and IL-8 levels in the stomach tissue resulting in impressive reductions in neutrophil infiltration. Similar results were reported by Moram et al 2016, where Indo increased the levels of TNF- α and IL-1 and the administration of red pepper and garlic bulb juices prevented the progression of Indo-induced ulcer formation [5].
NSAIDs-mediated destruction of gastric mucosa is also partially contributed by the imbalance between ROS generation and antioxidant enzymes/molecules as SOD and GSH [4]. Indo has been shown to induce ROS production through increasing lipid peroxidation and hydroxyl free radical, GSH depletion and inactivation of peroxidase activity [31]. Similarly, our results show that SOD and GSH were significantly reduced by Indo treatment. A decrease in the cell's antioxidant defense mechanisms is expected to be overpowered by free radicals thus causing cell damage and gastric injury. Oxidative stress can also induce cytokines production through activation of different transcription factors such as NF-κB, AP-1 and STAT [32]. The amplified cytokine production recruits more neutrophils at the site of injury which can further damage normal cells and aggravate the inflammatory response. Prior treatment with Caps increased the levels of SOD and GSH in a dose-dependent manner and protected the stomach tissue from Indo-induced damage.
Endothelial and neuronal NO synthases are expressed basally at the vascular endothelium and the neurons of the enteric nervous system of the gastrointestinal tract, respectively. Both forms mediate the production of NO at low physiological levels to maintain multiple physiological functions such as mucosal blood flow, mucosal integrity, and vascular tone [4, 33]. Induction of the inducible form (iNOS) in macrophages or even gastric epithelial cells by inflammation or infection generates a large amount of NO which in turn increases reactive oxygen species and peroxynitrite radicals and results in oxidative stress [33]. NSAID induced gastric damage also involve overexpression of iNOS and excessive release of NO. This was observed in our study, where Indo increased the concentration of NO by 3.3-folds compared to saline-treated rats with prior treatment with Caps extracts decreasing NO production in a dose-dependent manner.
It is worth mentioning that capsicum extract products of variable dose strength are available in the supplement market starting with a low dose strength of 100 mg to a high dose strength of 1000 mg with a recommended use of one tablet once or twice per day. Using the factor method that applies an exponent for body surface area (0.67), reviewed by Anroop B. Nair and Shery Jacob 2016, the 350 (ED50%) and 800 mg/kg/day dose in rat translates to a human equivalent dose of 46 and 105 mg/kg/day, respectively (3220 and 7350 mg/day, respectively for an average adult) [34]. These doses are indeed higher than those used in weight loss management, with the ED50% being closer to the maximum of 2000 mg/day being currently used for weight management. Therefore, we recommend conducting further dose escalation trials in humans to assess the safety and efficacy of capsicum extract in ulcer protection. Further, contribution to the observed gastroprotective effect from antioxidants components of Caps such as beta-carotene and vitamin C can not be excluded.
In conclusion, our results show that consumption of Caps extracts protected the rats from Indo-induced gastric ulcer in a dose dependent manner with a relatively low ED50% of 350 mg/kg. At higher dose levels (800 and 1600 mg/kg), the ulcer-protective effect was comparable to that produced by a 100 mg/kg/day Ran. This ulcer protective effect is potentially mediated via the inhibition of Indo-mediated induction of neutrophil infiltration, inflammatory cytokines (TNF- α and IL-8), NO and MDA and the inhibition of Indo-mediated depletion of GSH and SOD.
Competing Interests
The authors declare no competing interests.
Data availability Statement
The authors confirm that the data supporting the findings of this study are available within the article [and/or] its supplementary materials.
Funding Statement
No funding was received.
Author Contribution
OOG, AMF, AND MEE were involved in the conception and design, analysis and interpretation of the data. OOG wrote the first draft. OOG and MEE revised it critically for intellectual content and approved the final version to be published. All authors agree to be accountable for all aspects of the work.
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Egyptian Journal of Basic and Clinical Pharmacology
Vol. 11 (2021), Article ID 101541, 8 pages
doi:10.32527/2021/101541
Influence of Low and High Doses of Capsicum Extract on Indomethacin Induced Gastric Ulcer in Rats
Abstract
Background: Capsicum (Caps) has always been used as food spice. Recently, it has shown benefits in peptic ulcer but effective dose range and mechanisms mediating its effect are not known. This work is aimedto evaluate the gastroprotective effect of a wide dose range of Caps, compared with ranitidine (Ran), against indomethacin (Indo)-induced ulcer. Methods: 42 female adult Wistar albino rats were allocated into seven groups: 1) control (Cnt), 2) Indo (25 mg/kg p.o.), groups 3-6 were given Caps at 200, 400, 800 and 1600 mg/kg, p.o. prophylactically for 6 days. The last group was given 100 mg/kg, p.o. Ran for 6 days. Blood samples were withdrawn for analysis of MDA, GSH, NO, and SOD and stomachs were dissected for histopathological examinations and measurement of TNF-α and IL-8. Results: Caps replenished GSH and SOD and reduced TNF-α, IL-8, MDA and NO. It also reduced mucosal focal ulceration, neutrophil infiltration, ulcer index in a dose dependent manner. Importantly, Caps ulcer-protective effects were equivalent to those of 100 mg/kg Ran at 800 and 1600 mg/kg with an ED50% of 350 mg/kg. Conclusion: Caps extract possesses a dose-dependent ulcer-protective effect that is equivalent to that of Ran at relatively high doses.
Egyptian Journal of Basic and Clinical Pharmacology
Vol. 11 (2021), Article ID 101541, 8 pages
doi:10.32527/2021/101541
Influence of Low and High Doses of Capsicum Extract on Indomethacin Induced Gastric Ulcer in Rats
How to cite this article
Omneya O. Galal, Ahmed M. Fayez, and Marwa E. Elsherbiny, "Influence of Low and High Doses of Capsicum Extract on Indomethacin Induced Gastric Ulcer in Rats," Egyptian Journal of Basic and Clinical Pharmacology, Vol. 11, Article ID 101541, 8 pages, 2021. doi:10.32527/2021/101541.