research article - شرکت داروسازی گل دارو · objective: ulcerative colitis is a...

March 2014, Vol.12, No.2115Journal of Integrative Medicine

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● Research Article

Protective effect of ginger volatile oil against acetic acid-induced colitis in rats: a light microscopic evaluationAmir Rashidian1, Saeed Mehrzadi1, Ali Reza Ghannadi2, Parvin Mahzooni3, Samira Sadr4, Mohsen Minaiyan5

1. Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran2. Department of Pharmacognosy, School of Pharmacy and Pharmaceutical Sciences, Isfahan University

of Medical Sciences, Isfahan, Iran3. Department of Clinical Pathology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran4. Department of Pharmacology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran5. Department of Pharmacology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of

Medical Sciences, Isfahan, Iran

OBJECTIVE: Ulcerative colitis is a chronically recurrent inflammatory bowel disease of unknown origin. In the present study, the effect of ginger (rhizome of Zingiber officinale Roscoe) volatile oil on a rat model of colitis was evaluated. METHODS: Volatile oil of ginger with doses of 100, 200, and 400 mg/kg, prednisolone (4 mg/kg), or vehicle were administered orally to groups of male Wistar rats (n = 6) for 5 d. Animals were randomly divided into 6 groups, each group consisting of 6 rats. Colitis was induced by intracolonic instillation of 2 mL of 4% (v/v) acetic acid solution. All rats were sacrificed 24 h later and the tissue injuries were assessed macroscopically and histopathologically. RESULTS: Ginger volatile oil with all doses reduced colon weight/length ratio (P < 0.01) and the effects were similar to the reference drugs. Higher oral doses of volatile oil (200 and 400 mg/kg) reduced ulcer severity (P < 0.05 and P < 0.01), ulcer area (P < 0.01) and ulcer index (P < 0.01). On the other hand, evaluation of microscopic scores showed that the dose of 400 mg/kg of volatile oil was effective to reduce inflammation severity (P < 0.01) and inflammation extent (P < 0.05) compared to the control group.CONCLUSION: It is concluded that ginger volatile oil could effectively reduce symptoms of experimental colitis in a dose-dependent manner.KEYWORDS: ginger; Zingiber officinale; oils, volatile; acetic acid; colitis; rats

http://dx.doi.org/10.1016/S2095-4964(14)60011-XRashidian A, Mehrzadi S, Ghannadi AR, Mahzooni P, Sadr S, Minaiyan M. Protective effect of ginger volatile oil against acetic acid-induced colitis in rats: a light microscopic evaluation. J Integr Med. 2014; 12(2): 115-120.Received September 23, 2013; accepted January 13, 2014.Correspondence: Mohsen Minaiyan, PhD; Tel: +98-311-7922623; E-mail: [email protected]

1 Introduction

Inflammatory bowel disease (IBD) is a chronic inflammatory

condition affecting the gastrointestinal tract. It is divided into two major categories: ulcerative colitis and Crohn’s disease. Ulcerative colitis is a disease of the colon mainly while Crohn’s disease is a condition affecting all parts of

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March 2014, Vol.12, No.2 116 Journal of Integrative Medicine

gastrointestinal tract. The cause of inflammatory bowel disease is unknown but several factors have been implicated. These include environmental factors, genetic factors, microbial pathogens, defects in immunoregulation and altered levels of inflammatory mediators[1-3]. Inflammatory mediators such as cytokines, eicosanoids and reactive oxygen metabolites play a crucial role in the development and persistence of the disease[4-6].

Glucocorticoids and aminosalicylates have been used for the treatment of IBD, but the side effects remain a major clinical problem. Various experimental colitis models have been established to screen drug effectivity against IBD and acetic acid-induced colitis. This research includes any animal model which mimics some of the acute inflammatory responses in ulcerative colitis[7-9].

Dietary supplements containing botanical products are used by the public for a wide range of health-related problems, including chronic inflammatory diseases such as chronic obstructive pulmonary disease, asthma and rheumatoid arthritis. A number of these botanical supplements have been used for centuries in Ayurvedic medicine, and it has been proposed that they have anti-inflammatory actions. Ginger, powdered rhizome of the herb Zingiber officinale, is widely used as a spice throughout the world. In Ayurvedic medicine, ginger has traditionally been used in the treatment for rheumatism, nervous disease, gingivitis, toothache, asthma, stroke, constipation and diabetes[10].

Ginger extract has been reported to have anti-inflammatory[11] and antioxidant effects[12,13]. Volatile oil of ginger has the capability to modulate the function of lymphocytes and cellular immune response. These results suggest that the volatile oil of ginger influences both cell-mediated immune response and nonspecific proliferation of T lymphocytes, and may exert beneficial effects in a number of clinical conditions such as chronic inflammation and autoimmune diseases[14]. In the present study, the effects of ginger (rhizome of Zingiber officinale Roscoe) volatile oil on a rat model of colitis was evaluated.

2 Materials and methods

2.1 AnimalsMale Wistar rats (180-200 g) were obtained from the

Animal Center, Faculty of Pharmacy, Isfahan University of Medical Sciences, Isfahan, Iran. A 12-h light, 12-h dark cycle was maintained. The animals, being kept under standard conditions, had access to a standard diet and clean drinking water.2.2 Preparation and the main components of ginger volatile oil

Dried rhizome of ginger was provided by the Herbarium Center of Goldaru Co. Ltd., Isfahan, Iran. The essential oil was isolated by hydrodistillation of the air-dried powdered rhizome

of the plant for 3 h according to the method recommended in the European Pharmacopoeia (2002)[15]. Tween-80 solution (1%) in distilled water was used to solubilize the volatile oil of ginger as a suspension before being used.2.3 Analysis of the essential oil

The essential oil was analyzed by gas chromatography-mass spectrometry (GC/MS) on a Hewlett Packard 6890 MS selective detector coupled with Hewlett Packard 6890 gas chromatograph equipped with a crosslinked 5% phenyl-methy siloxane, HP-5MS capillary column (30 m × 0.25 mm; film thickness 0.25 μm) operated under the following conditions: carrier gas, helium with a flow rate of 2 mL/min; column temperature, 60-275 ℃ at 4 ℃/min; injector and detector temperature, 280 ℃; volume injected, 0.1 μL of the oil; split ratio, 1:50. The MS operating parameters were as follows: ionization potential 70 eV, ionization current 2 A, ion source temperature 200 ℃, resolution 1 000.

Identification of oil components was based on computer matching with the Wiley 275 L. library as well as comparison of the fragmentation patterns of mass spectra with those reported in the literature[16-18]. The relative percentage of the oil constituents was calculated from the peak areas.2.4 Chemicals

Prednisolone powder and hydrocortisone acetate enema were procured from Iran Hormone Pharmaceutical Co. (Tehran, Iran) and Valeant Pharmaceutical Co. (Saint-Laurent, Canada), respectively. All of organic solvents were of analytical grade and provided by Merck (Germany).2.5 Animal grouping

Six groups of rats (n=6) were included in the study. Normal control group received the drug delivery vehicle (normal saline 2 mL/kg, orally) without induction of colitis. Rats in model control group received the vehicle (normal saline 2 mL/kg, orally) and were subjected to the colitis induction procedure. Volatile oil treatment groups received low, medium or high doses of volatile oil (100, 200, and 400 mg/kg) orally in a volume of 1 mL for 5 consecutive days before ulcer induction. Prednisolone group received prednisolone (4 mg/kg, orally) for 5 consecutive days before ulcer induction.2.6 Experimental protocol

The test samples including solutions or suspensions of drugs or plant extract were freshly prepared. The plant extraction was prepared as 1% (v/v) Tween-80 in suspension form. Acute colitis was induced by acetic acid using a technique introduced by Mascolo et al[19]. Briefly, rats were fasted for 36 h with access to water ad libitum and observed to ensure their health before induction of colitis. The rats were lightly anesthetized with ether. A flexible plastic catheter with an outside diameter of 2 mm was inserted 8 cm into the colon via the anus. Diluted 4% acetic acid (2 mL) was injected into the colon and the rats were maintained in a



head-down position for 5 min to prevent solution leakage. In the normal control group, normal saline was instilled. Twenty-four hours after colitis induction, rats were sacrificed using ether anesthesia and colonic biopsies were taken for macroscopic scoring and histopathological examination.2.7 Assessment of colon macroscopic damage

A segment of the colon, 8 cm in length and 3 cm proximal to the anus was excised, opened longitudinally and washed in saline buffer. These tissue specimens were weighed and the wet weight/length ratio was measured in all rats. A pathologist unaware of treatment conditions recorded macroscopic and histological damage. The criteria for macroscopic evaluation relied on a previously validated scoring system from 0-4 according to Morris et al[20]. The scores were: 0 = no ulcer; 1 = mucosal erythema only; 2 = mild mucosal edema, slight bleeding or slight erosion; 3 = moderate edema, bleeding ulcers or erosions; 4 = severe ulceration, erosions, edema and tissue necrosis. Ulcer area was measured using 3M® scaled surgical transparent tape, which was fixed to a light and transparent sheet. Each cell on the tape was 1 mm2 in area and the number of cells covering the ulcerated area of each specimen was counted. Ulcer index was measured by summing the ulcer score and the ulcer area of each tissue specimen. Ulcer index was calculated according to the following formula[21]:

UI=UN+US+UA×10-1, where UI = ulcer index, UN = ulcer number, US = ulcer score, and UA= ulcer area.

2.8 Assessment of colon histological damageFor histological examination, colon tissues were separately

fixed in 10% formalin, dehydrated, paraffin embedded, processed, sectioned as 4 μm-thick sections, and stained with haematoxylin and eosin (HE). Inflammation severity (0 = none, 1 = slight, 2 = moderate, 3 = severe) and extent (0 = none, 1 = mucosa, 2 = mucosa and submucosa, 3 = transmural) as well as crypt damage (0 = none, 1 = basal 1/3 damaged, 2 = basal 2/3 damaged, 3 = only surface epithelium intact) were assessed in HE-stained, coded sections using a modification of a validated scoring scheme described by Cooper et al[22] and Dieleman et al[23]. Total colitis index was gained by summing 3 subscores (inflammation severity, inflammation extent, and crypt damage). Histological damages were investigated using a Zeiss® microscope equipped with a Sony® color video camera for digital imaging.2.9 Statistical analysis

The results were reported as mean ± standard deviation. The statistical analysis was conducted using one-way analysis of variance by SPSS 20.0. Group differences were calculated by Dunnett’s t test at a significance level of 0.05.

3 Results

3.1 Analysis of the essential oilEighteen constituents were characterized accounting for

97.67% of the total oil components detected, which are listed in Table 1. The principal constituent of ginger oil was zingiberene (28.05%), a sesquiterpene hydrocarbon, followed by ar-curcumene (14.06%) and α-sesquiphellandrene (12.91%). Other compounds included β-bisabolene (13.15%) and sabinene (9.32%).

Table 1 Volatile oil constituents of the essential oil of ginger

No. Compound Percentage of total area (%)1 Zingiberene 28.052 Ar-Curcumene 14.063 β-Bisabolene 13.154 α-Sesquiphellandrene 12.915 Sabinene 9.326 Camphene 4.067 β-Panasinsene 2.478 α-Elemene 2.199 Thujopsene 2.01

10 γ-Elemene 1.8311 Germacrene 1.5412 Silane 1.0513 Aromadendrene 1.0414 Verbenone 0.9415 α-Cubebene 0.9116 Elemol 0.8417 Isoborneol 0.7718 Farnesol 0.53

3.2 Macroscopic presentationNo mortality was observed in rats receiving intracolonic

4% acetic acid (2 mL) solution. Acetic acid treatment caused increased wet weight/length ratio in the model group rats (Table 2 and Figure 1A). Pretreatment with prednisolon reduced the damage score (P<0.01), ulcer area (P<0.01), ulcer index (P<0.01) and wet weight/length ratio (P<0.01) significantly compared to the model control group (Table 2 and Figure 1B). Ginger volatile oil reduced the intensity of inflammation, ulcer area and ulcer index in a dose-dependent manner as shown in Table 2 and Figures 1C, 1D and 1E. The wet weight/length ratio was reduced at all doses of oral treatments by ginger volatile oil significantly compared with the model control groups (P<0.01). No significant difference was found between the prednisolone group and the ginger volatile oil (400 mg/kg) group.3.3 Histological evaluation

The histopathological features of the model control group animals included transmural necrosis, oedema and diffuse inflammatory cell infiltration in the mucosa, desquamated



areas and loss of epithelium. An infiltrate consisting of mixed inflammatory cells was observed (Figure 2B). The normal control group did not develop these responses (Figure 2A).

Rats treated with prednisolone (Table 2 and Figure 2C), or ginger volatile oil (Table 2 and Figure 2D) exhibited significantly attenuated histopathological scores including: involvement percentage, inflammation severity, inflammation extent, crypt damage and total colitis index, which were more obvious with ginger at 200 and 400 mg/kg oral doses.

4 Discussion

Induction of colitis by acetic acid in rats is one of standardized

methods to produce an experimental model of IBD. Several major causative factors such as enhanced vasopermeability, prolonged neutrophil infiltration and increased production of inflammatory mediators are present in this induced animal model[24].

The present study demonstrated that treatment with ginger lead to a dose-dependent reduction in inflammation and acute colonic damage induced by acetic acid. This finding was verified in both macroscopic and histological examina-tions. In our study, oral prednisolone was used as a reference drug to delineate the efficacy of a test substance. It is assumed that oral pretreatment with prednisolone for a period of 5 consecutive days causes a better condition for absorption and systemic availability of active drugs. The same results

Table 2 Effects of ginger volatile oil on the macroscopic parameters of colitis induced by acetic acid in rats(Mean ± standard deviation)

Group n Ulcer score Ulcer area (cm2) Ulcer index Weight/length ratioNormal control (saline, 2 mL/kg, oral) 6 0.00±0.00 0.00±0.00 0.00±0.00 84.33±9.91Model control (vehicle, 2 mL/kg, oral) 6 2.83±0.75 6.81±0.72 9.64±1.37 146.67±3.72**

Prednisolone (4 mg/kg, oral) 6 1.04±0.38 △△ 1.01±0.26 △△ 2.17±0.48 △△ 92.17±7.22 △△

Volatile oil low-dose (100 mg/kg, oral) 6 2.00±0.63 5.47±0.58 △△ 7.47±1.15 △△ 109.83±8.21 △△

Volatile oil medium-dose (200 mg/kg, oral) 6 1.67±0.82 △△ 3.89±0.40 △△▲▲ 5.55±1.19 △△▲▲ 103.00±3.16 △△

Volatile oil high-dose (400 mg/kg, oral) 6 1.17±0.41 △△ 1.13±0.15 △△▲▲□□ 2.29±0.47 △△▲▲□□ 97.33±4.32 △△▲

**P<0.01, vs normal control group; △△ P<0.01, vs model control group; ▲ P<0.05, ▲▲ P<0.01, vs volatile oil low-dose group; □□ P<0.01, vs volatile oil medium-dose group.

Figure 1 Macroscopic presentation of acetic acid-induced colitis in ratsA: Colitis in control group treated with vehicle; B: Colitis in prednisolone-treated group; C, D and E: Colitis in ginger volatile oil-treated group, 100, 200 and 400 mg/kg, respectively.

Table 3 Effects of ginger volatile oil on histopathologic parameters of colitis induced by acetic acid in rats(Mean ± standard deviation)

Group n Inflammation severity

Inflammation extent Crypt damage Involvement

percent (%)

Normal control (saline, 2 mL/kg, oral) 6 0.00±0.00 0.00±0.00 0.00±0.00 0.00±0.00Model control (vehicle, 2 mL/kg, oral) 6 2.83±0.75 2.83±0.75 3.83±0.41 3.83±0.41Prednisolone (4 mg/kg, oral) 6 1.04±0.39 △△ 1.57±0.7 △△ 1.04±0.39 △△ 1.04±0.39 △△

Volatile oil low-dose (100 mg/kg, oral) 6 2.17±0.41 2.17±0.41 2.83±0.41 △△ 2.17±0.75 △△

Volatile oil medium-dose (200 mg/kg, oral) 6 2.00±0.63 △ 1.83±0.75 △ 2.50±0.55 △△ 1.17±0.52 △△▲▲

Volatile oil high-dose (400 mg/kg, oral) 6 1.17±0.41 △△▲▲□□ 1.67±0.82 △ 1.17±0.41 △△▲▲□□ 1.17±0.41 △△▲▲

△ P<0.05, △△ P<0.01, vs model control group;▲▲ P<0.01, vs volatile oil low-dose group; □□ P<0.01, vs volatile oil medium-dose group.



were obtained using medium and high oral doses of ginger volatile oil.

In recent years, clinical trials have shown that ginger can be used successfully in the treatment of a number of conditions. In vitro studies have shown that a large range of ginger constituents inhibit the production of nitric oxide, inflammatory cytokines and enzymes such as prostaglandin synthase and arachidonate-5-lipoxygenase in a dose-dependent manner. The latter in turn inhibits the synthesis of prostaglandins and leukotrienes from cyclooxygenase (both 1 and 2) and lipoxygenase respectively[25,26].

It has been demonstrated that ginger could significantly reduce inflammation compared to conventional drugs in animals[27,28]. A retrospective human survey suggested a minimum effective dose of 1 g per day, with higher doses proving to be more effective. Nevertheless, subsequent human trials used much lower doses and obtained spectacular results. Importantly, these treatments resulted in fewer side effects than conventional drugs, including non-steroidal anti-inflammatory drugs and corticosteroids[29].

Ginger’s high antioxidant value has been proved to be highly effective with its ability to scavenge a number of free radicals and protect cell membrane lipids from oxidation in a dose-dependent manner[25]. Rat study showed that ginger significantly lowered induced lipid peroxidation and raised the level of antioxidant enzymes, together with serum glutathione, and demonstrated that ginger has an antioxidant effect equal to that of ascorbic acid[30]. Volatile oil of ginger is able to modulate the function of lymphocyte and cellular immune responses, as well as the nonspecific proliferation of T lymphocytes. It may also exert beneficial effects in a number of clinical conditions such as chronic inflammation and auto-immune diseases[14].

In conclusion, the present study suggests that pretreatment with ginger ameliorates symptoms of acetic acid-induced colitis in rats and this protective effect may at least in part, be due to their antioxidant and anti-lipoperoxidative actions. Our results suggest that ginger may be beneficial in the treatment of colon mucosal damage caused either experi-

mentally or through IBD. It is suggested that more studies are needed to establish the mechanisms involved and to isolate the active constituents of ginger volatile oil which are responsible for its anti-inflammatory actions.

5 Conflict of interests

The authors declare that they have no conflict of interests.

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