|Year : 2021 | Volume
| Issue : 1 | Page : 29-34
Evaluation of the therapeutic effect of Achillea wilhelmsii C. Koch aqueous extract in acetic-acid-induced ulcerative colitis in rat
Ali Ghobadi1, Mohammad Heydarian2, Gholamreza Bahrami2, Leila Hosseinzadeh2, Yalda Shokoohinia2, Mohammad Hosein Farzaei2, Hosna Khazaei2, Kimia Aghaei2
1 Research Institute for Islamic and Complementary Medicine, Iran University of Medical Sciences, Tehran, Iran
2 Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
|Date of Submission||07-Jan-2020|
|Date of Acceptance||10-Sep-2020|
|Date of Web Publication||31-May-2021|
Dr. Mohammad Hosein Farzaei
Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah.
Source of Support: None, Conflict of Interest: None
Context: Ulcerative colitis (UC) is a chronic, idiopathic, and recurrent disease with unknown etiology. Achillea wilhelmsii has been introduced as a herbal remedy for gastrointestinal ulcers and UC in traditional Persian medicine. Aims: We examined the effectiveness of A. wilhelmsii aqueous extract against acetic-acid-induced UC in rats. Settings and Design: Fifty-six male Wister albino rats weighing 180–200g were randomly divided into eight groups and after induction of UC were treated with five doses of aqueous extract of A. wilhelmsii.Materials and Methods: After induction of UC by acetic acid, the aerial parts of A. wilhelmsii (6.25, 12.5, 25, 50, and 100 mg/kg) were administered orally. On 11th day, the animals were euthanized by overdose of ether inhalation and the intestinal tissue was rapidly dissected for macroscopic, histological, and microscopic scores. Statistical Analysis Used: Data were analyzed by stats Directver.2.7.9 (SAS, Cary, North Carolina). One-way analysis of variance (ANOVA) followed by Newman–Keul’s post hoc test for multiple comparisons. A value of P < 0.05 was considered as significant level. Results were expressed as mean ± standard error of the mean (SEM). Results: All doses of A. wilhelmsii extract significantly reduced macroscopic and microscopic scores of colitis without significant changes in bodyweight of animals. Conclusions: Treatment of the rats with A. wilhelmsii extract improved UC via its anti-inflammatory, antioxidant, and antimicrobial activities. According to the results of this study, A. wilhelmsii has a therapeutic effect against acetic-acid-induced UC in the animal model.
Keywords: Achillea wilhelmsii C. Koch, antioxidant, herbal remedy, inflammation, ulcerative colitis
|How to cite this article:|
Ghobadi A, Heydarian M, Bahrami G, Hosseinzadeh L, Shokoohinia Y, Farzaei MH, Khazaei H, Aghaei K. Evaluation of the therapeutic effect of Achillea wilhelmsii C. Koch aqueous extract in acetic-acid-induced ulcerative colitis in rat. J Rep Pharma Sci 2021;10:29-34
|How to cite this URL:|
Ghobadi A, Heydarian M, Bahrami G, Hosseinzadeh L, Shokoohinia Y, Farzaei MH, Khazaei H, Aghaei K. Evaluation of the therapeutic effect of Achillea wilhelmsii C. Koch aqueous extract in acetic-acid-induced ulcerative colitis in rat. J Rep Pharma Sci [serial online] 2021 [cited 2021 Oct 21];10:29-34. Available from: https://www.jrpsjournal.com/text.asp?2021/10/1/29/317231
| Key Messages:|| |
Achillea wilhelmsii C. Koch aqueous extract can be considered as a potent treatment against UC induced by acetic acid in the rat model. This therapeutic effect was comparable with the standard drug. It has been suggested that these therapeutic effects are due to its anti-inflammatory, antioxidant, and antimicrobial actions.
| Introduction|| |
Inflammatory bowel disease (IBD) is a chronic, idiopathic, and recurrent disease with two major subtypes, including Crohn’s and colitis. Crohn’s disease (CD) can involve all parts of the gastrointestinal tract, whereas UC just affects colonic mucosa. Increased inflammatory mediators due to immune defects or infectious agents are the most important factors involved in IBD pathogenesis. During the progression of IBD, the immune system has not appropriate response against the infectious agents to the initial state and the intestinal tissue remains inflamed; even it may lead to invasive cancer. These inflammatory responses generally including overexpression of pro-inflammatory cytokines such as interleukin-1ß (IL-1ß), interferon-ɣ (INF-ɣ), tumor necrosis factor-α (TNF-α), and interleukin-23 (IL-23).,,, IBD first spread in high-income countries such as Northern Europe and North America with the high percentage. So that 1.4 million persons in the US and 2.2 million persons in Europe have IBD. It has spread in Asia and Southern Europe with an annual incidence of 6.3 per 100,000 persons for UC and 20.2 per 100,000 persons for CD. IBD usually occurs between the ages of 15 and 30 and rarely occurs in patients with 50–60 years old. The pathogenesis of IBD is not clear yet but it has been suggested that environment, geographic location, and smoking are important factors that can lead to IBD in a genetic background.,, Anti-inflammatory drugs such as corticosteroids (prednisolone, methylprednisolone, and budesonide), and amino salicylates have been used by patients suffering from IBD. 5-aminosalicylic acid (5-ASA) can be used orally or topically. Mesalamine, sulfasalazine, and olsalazine are available for oral use. Sulfasalazine cleaved by anaerobic bacteria in bowel to 5-ASA and sulfa pyridine (SP). Recent researches showed that therapeutic effect of sulfasalazine is due to ASA and SP that causes diarrhea, abdominal pain, nausea, and vomiting., Because of several side effects of drugs used for IBD treatment, their long-term usage is limited.
Many researches showed the beneficial effect of herbal remedies including anti-inflammatory, antioxidant, and anticancer, without above side effects that are due to treatment with chemical drugs.,Achillea wilhelmsii C. Koch is a perennial herb that belongs to Asteraceae family and includes more than 100 species worldwide,, especially central and western areas of Asia and Europe., Several species of Achillea genus are known as Bumadaran in Persian.
Achillea wilhelmsii contains saponins, alkaloids, volatile oils, terpenoids, and flavonoids. It has been shown that antioxidant activity as well as antimicrobial properties against Escherichia coli and candida. It has been shown that A. wilhelmsii has a stimulatory effect on humoral and cellular immunity and increases immune response due to its flavonoids and saponins content that stimulates humoral response and has immunomodulatory activity. It has also been used as antispasmodic immune system regulator, antiplatelet activity, antitumor,, antiulcer, cholera therapist, and antibacterial.,, This study was conducted to investigate the therapeutic effect of A. wilhelmsii aqueous extract in the experimental model of colitis.
| Subjects and Methods|| |
Preparation of A. wilhelmsii aqueous extract
Achillea wilhelmsii was gathered from Bisotun area in Kermanshah province, west of Iran, in May 2008 and authenticated by Dr. Masoumi, and voucher specimen (NO: 2729) was deposited in the central herbarium of faculty Agriculture Razi University of Kermanshah. Aerial parts of the plant were air-dried in shade and powdered by electric milling to create more surface contact with the solvent. Maceration method was used to prepare the extract. 100g of the powder was solved in 100 mL double-distilled water and boiled for 30 min. The extract was cooled down and filtered with Whatman filter paper no.1 and extract was stored at 4°C for further use.
Fifty-six male Wister-albino rats weighing 180–200g were accommodated under standard laboratory condition at normal temperature (23±2°C), and 12 h light/dark cycle. Ethical rules of the investigation on animals were approved by the committee of Kermanshah University of Medical Sciences (KUMS). During the adaptation, animals were fed with standard food and water for 1 week.
Induction of colitis and treatment
Acetic-acid-induced colitis, which is similar to human UC; it was first described by Macpherson according to Kojima et al.’s method. It is a laboratory and experimental model of human IBD. According to Farzaei et al.’s investigation, rats were fasted for 24 h and then were anesthetized with intraperitoneal (IP) injection of ketamine (10 mg/kg) with the right side position; after that, 1 mL of acetic acid (4% v/v in 0.9% saline) was instilled through rectum via rubber cannula (8 cm long). Because of the preventing of acetic acid leakage, we placed rats in a supine position. Sulfasalazine was used as the standard drug.
Rats were randomly divided into eight groups (n = 8). Induction of colitis was performed by instillation of acetic acid. Animals were grouped as follows: (1) animals without UC and any treatment, (2) animals with UC and received 6.25 mg/kg/d of A. wilhelmsii extract, (3) animals with UC and received 12.5 mg/kg/d of A. wilhelmsii extract, (4) animals with UC and received 25 mg/kg/d of A. wilhelmsii extract, (5) animals with UC and received 50 mg/kg/d of A. wilhelmsii extract, (6) animals with UC and received 100 mg/kg/d of A. wilhelmsii extract, (7) animals with UC that received distilled water, and (8) animals with UC and treated by 100 mg/kg/day sulfasalazine. All treated groups received A. wilhelmsii extract dissolved in water and administered orally by gavage. Treatment was administered to the animals for 10 days, 1 week before induction of colitis up to 3 days after induction of colitis. On the 11th day, the animals were euthanized by an overdose of ether inhalation and intestinal tissue was rapidly dissected.
Microscopic and macroscopic assessment of colonic damage
Both macroscopic and histopathologic assessments were performed in this research. According to Farzaei et al.’s method, the samples were sliced in two pieces: one piece for histopathology assessment and the other for measuring biomarkers that were weighed and maintained at –20ºC for 24 h.
For macroscopic evaluation, on the 11th day, pieces were separated from colon at 5 cm in length and fixed in 10 mL formalin 10%. Macroscopic scoring was performed by using a method based on Mustafa et al.’s study, according to scale ranging from 0 to 4 as shown in [Table 1].
Very thin cut of colonic tissue should be made for the light to pass the through and fixed in 10% formalin in phosphate-buffered saline and then stained with hematoxylin and eosin. This thin cut was scored by histopathologist according to scoring system shown in [Table 2].,
|Table 2: Histological assessment of biopsy specimen thickness in animals with UC induced by acetic acid inoculation|
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Data were analyzed by stats Directver.2.7.9 (SAS, Cary, North Carolina) One-way analysis of variance (ANOVA) followed by Newman–Keul’s post hoc test for multiple comparisons. A value of P < 0.05 was considered as significant level. Results were expressed as mean ± standard error of the mean (SEM).
| Results|| |
Macroscopic and microscopic assessment of colonic damage
Results of macroscopic score are shown in [Figure 1]. According to the chart, higher macroscopic scores are seen in control group. Intra-rectal administration of acetic acid to the control group exhibited ulceration, adhesion, wall thickening, and severe inflammation in comparison with the normal group. The best healing activity among treated groups belonged to 12.5 mg/kg of A. wilhelmsii extract. Higher and lower doses reduce the therapeutic effect of A. wilhelmsiias. As well as administration of sulfasalazine (100 mg/kg) improves ulcerating, adhesion, wall thickening, and inflammation than other groups and have lowest macroscopic score. Macroscopic results show that the score of treatment group with sulfasalazine was very similar to the treatment group with 12.5 mg/kg of A. wilhelmsii extract.
|Figure 1: Ulcer score in different groups with UC receiving Achillea wilhelmsii extract|
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Results of microscopic score are shown in [Figure 2]. According to [Table 2], microscopic evaluation of control group (Score 5) showed severe edema, hemorrhage, necrosis, ulceration, and mucosal and submucosal polymorphonuclear. In the positive control group (sulfasalazine), minor lesions and mild mucosal inflammation was observed. In the treatment group with 100 mg/kg of A. wilhelmsii extract, crypt destruction, submucosal inflammation, and polymorphonuclear was observed. In treatment groups with 25 and 50 mg/kg of A. wilhelmsii extract, mild inflammation, diffuse destruction of crypts, and edema in some parts were observed. As well as, colon features were normal in normal groups. Finally, according to microscopic evidence as only mucosal inflammation was seen in the sulfasalazine group, so it is expected to have the least microscopic score (Score 1) like the treatment group with 12.5 mg/kg of A. wilhelmsii extract (Score 1).
|Figure 2: Histological assessment of colon tissue in different groups. Microscopic evaluation of control group (Score 5) showed intense transdermal inflammation and/or diffuse necrosis (A) and sever crypt destruction (B). Control+ group (Score 1) showed minimal mucosal inflammation (A), in AW-50 (Score 2) polymorphonuclear (PMN) accumulation (A) and destruction of crypts (B), in AW-25 group (Score 2) creation of crypts and submucosal inflammation and mild PMN accumulation (B), in AW-100 (Score 3) PMN accumulation (A) and destruction of crypts (B) were observed|
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| Discussion|| |
This study investigates the therapeutic effects and possible mechanism and chemical constituents of A. wilhelmsii aqueous extract. Our research showed the antimicrobial effects of A. wilhelmsii on UC by laboratory evidence, microscopic and macroscopic tissue studie,s and its effects were comparable with sulfasalazine. The reduction in microscopic and macroscopic score is due to administration of different doses of A. wilhelmsii (6.25, 12.5, 25, 50, and 100 mg/kg) that dramatically improvement of UC was observed in treatment group with 12.5 mg/kg of A. Wilhelmsii extract. Several studies showed that in proinflammatory situation, some of the cytokines such as TNF-α and IL-6 produced in large quantities leading to activation of mesenchymal cells and cause exacerbate in the inflammatory response and severe tissue damage which induce the production of other cytokines by cells that eventually lead to intestinal necrosis, edema and neutrophil infiltration of the tissue., Researches showed that blocking inflammatory mediators reduces acute and chronic disorders caused by them. Some of the cellular and animal studies have shown the anti-inflammatory and inhibitory effects of A. wilhelmsii extract on inflammatory cytokines. Studies show that A. wilhelmsii extract does its effect by increasing macrophages and B-lymphocytes levels. Flavonols as one of the active compounds of A. wilhelmsii extract can stimulate proliferation of human peripheral blood leukocyte and raises the activity of helper T cells, cytokines, interleukin 2, g-interferon, and macrophages so it can be considered as a potent immunomodulatory herb. IBD is the result of improper immune response (the phenomenon of the autoimmunity and non-auto immunity). Important characteristic of UC is bloody diarrhea and in more severe cases form bloody stool with dyspepsia before extraction, but Crohn’s is heterogeneous disease and its manifestations depending on where it is involved and symptoms usually include: non-bloody diarrhea, fever, dyspepsia, and lose weight., Among the animal models used to UC studies, mice are the most appropriate model. UC induced by acetic acid inoculation because it induces colitis similar to human colitis in animal models., Acetic acid does not directly cause intestinal inflammation but it induces IBD by overexpression of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-23; so acetic acid is used to investigate the therapeutic effect of medications. For this purpose, these medications should be taken 24 h after the administration of acetic acid.Achillea wilhelmsii has beneficial effects such as hypertensive, hepatoprotective, and gastric acid output. HPLC chromatogram of the A. wilhelmsii aqueous extract shows this extract contains isoschaftoside, schaftoside, vicenin 2, vicenin 3, caffeic acid, isovitexin, leucodin; A. wilhelmsii aqueous extract shows a high content of phenols and flavonoids. Mahmoudabady et al. showed that flavonoids are one of the most common antioxidant and have a beneficial effect on reducing oxidative stress. As well as, the antioxidative activity of A. wilhelmsii extract (75 mg/kg) causes significant changes in hematologic parameters such as mean corpuscular hemoglobin concentration (MCHC) and mean corpuscular hemoglobin (MCH) reduction. Non-toxicity is confirmed by histopathologic and microscopic investigation. Niazmand et al. showed that A. wilhelmsii inhibits extracellular calcium entry into cells by blocking voltage-dependent channels and cause vasodilation in the aorta.
| Conclusion|| |
The result of this study showed that the aqueous extract of A. wilhelmsii treated acetic-acid-induced UC in rats. As well as, macroscopic and microscopic scores in all groups that received A. wilhelmsii were less than control group, but the most effective dose of A. wilhelmsii extract was 12.5 mg/kg. In this study the necessity of herbal remedies and its superiority compared with chemical treatments was emphasized. As well as therapeutic effects of A. wilhelmsii were discussed in detail and showed its best therapeutic effect at 12.5 mg/kg. Hope to be considered as a complementary treatment of colitis in the near future.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]