|Year : 2017 | Volume
| Issue : 4 | Page : 198-205
Effects of nicorandil and dexamethasone on ovalbumin-induced bronchial asthma in a rat model
Waleed Barakat El-Bahouty
Department of Pharmacology, Faculty of Medicine, Tanta University, Tanta, Egypt
|Date of Submission||05-Dec-2016|
|Date of Acceptance||06-Sep-2017|
|Date of Web Publication||12-Mar-2018|
Waleed Barakat El-Bahouty
10th Omar Ebn Abdel-Aziz, Tanta, 31511
Background Recent researches suggest that oxygen and its related species (oxidants) may contribute to the pathogenesis of a number of important lung diseases. Endogenous and exogenous reactive oxygen species play a major role in airway inflammation and are determinants of asthma severity.
Aim The aim of this work was to study the antioxidant activity of nicorandil drug in bronchial asthma as an attempt to minimize the dose and side effects of using corticosteroids.
Materials and methods The study was carried out in 50 rats weighing 120–150 g, subdivided into five groups each of which consisted of 10 rats. Group 1 rats were given normal saline intragastric and served as the control group; group 2 rats were given ovabumin; group 3 received dexamethasone 1 h before ovalbumin (OVA) challenge till last challenge (after 24 days); group 4 received nicorandil 1 h before OVA challenge till last challenge (after 24 days); group 5 received dexamethasone and nicorandil 1 h before OVA challenge till last challenge (after 24 days). At the end of the experiment (24 days), animals were kept on overnight fasting and were killed by decapitation. Lung sections were collected and then divided into two portions: one for histopathology and the other part of lung sections were homogenized and prepared for estimation of lung malondialdehyde, glutathione peroxidase, and tumor growth factor-β1 (TGF-β1). Blood samples were collected from all studied groups and lifted for clotting at 37°C and then centrifuged for separation of plasma for estimation of TGF-β1, tumor necrosis factor-α, and interleukin-6.
Results The study showed that nicorandil administration whether alone or with dexamethasone, significantly reduced serum and tissue levels of inflammatory markers (TGF-β1, tumor necrosis factor-α, interleukin-6) and also significantly decreased lung malondialdehyde, TGF-β1 together with elevation of antioxidant activity presented by elevation of serum glutathione peroxidase.
Keywords: dexamethasone, nicorandil, ovalbumin-induced asthma, rats
|How to cite this article:|
El-Bahouty WB. Effects of nicorandil and dexamethasone on ovalbumin-induced bronchial asthma in a rat model. Tanta Med J 2017;45:198-205
|How to cite this URL:|
El-Bahouty WB. Effects of nicorandil and dexamethasone on ovalbumin-induced bronchial asthma in a rat model. Tanta Med J [serial online] 2017 [cited 2018 Mar 24];45:198-205. Available from: http://www.tdj.eg.net/text.asp?2017/45/4/198/227120
| Introduction|| |
Asthma is a chronic inflammatory lung disease involving complex interactions between numerous cell types and mediators that result in airway reactivity and airflow limitation . The pathogenesis of chronic obstructive lung disorders such as asthma and chronic obstructive pulmonary diseases (COPD) is complex. It involves both airway inflammation  with an oxidant/antioxidant imbalance .
Reactive oxygen species can lead to lung injury as a result of direct oxidative damage to epithelial cells and cell shedding . Reactive oxygen species have been shown to be associated with the pathogenesis of asthma by evoking bronchial hyper-reactivity  as well as by directly stimulating histamine release from mast cells and mucus secretion from airway epithelial cells .
The mechanism by which oxygen radicals cause asthma pathology is oxidation or nitration of proteins, lipids, or DNA to cause dysfunction of these molecules. In addition, the physiological antioxidant system is impaired in asthma, possibly because of inflammation .
Asthma is managed with use of long-acting adrenergic receptor agonists as bronchodilators and low-dose inhaled glucocorticosteroids . However, corticosteroids have a number of important limitations. First, steroid resistance, where a subpopulation of patients with asthma shows poor response to drugs. Second, corticosteroids cannot be used at the highest concentrations in young children. Third, corticosteroids have only limited efficacy in preventing and reversing airway remodeling changes . Fourth, long-term administration of glucocorticoids has been shown to result in mitochondrial dysfunction as well as oxidative damage of the mitochondria and nuclear DNAs .
Nicorandil, a mitochondrial ATP-dependent potassium channel (KATP) with NO donor (nitrate-like) activity, is used in the treatment of angina and heart failure , has antioxidant activity . However, the effect of nicorandil against ovalbumin (OVA)-induced bronchial asthma has not yet been clarified.
The aim of this study was to minimize the dose and hence the side effects of corticosteroids in treating bronchial asthma by using nicorandil, which is a mitochondrial ATP-dependent potassium channel opener with NO donor activity.
| Materials and methods|| |
Animals and experimental design
The animals and the experimental design fulfil the ethical criteria.
- Dexamethasone was purchased from Sigma Co. (Nasr City, Egypt), prepared in saline and administered orally at a dose of 1 mg/kg .
- Nicorandil (Adancor) was purchased from Merck Serono Co. (Darmstadt, Germany). It was suspended in crboxy methyl cellulose 0.5% and was given orally at doses of 3 mg/kg.
Ovalbumin (grade III) and aluminum hydroxide were purchased from Sigma Aldrich Chemical Co. (St. Louis, Missouri, Unites States).
Crboxy methyl cellulose 0.5%: purchased from Al-Gomhoria Pharmaceutical Company (EL- Geish str. Tanta, Egypt) in the form of powder, it was prepared as 0.5 g/100 ml in distilled water.
Animals and experimental design
A total of 50 rats obtained from a local animal house, each weighing 120–150 g, were used throughout the experiment. They were kept under similar housing conditions and offered food and water ad libitum. They were subdivided randomly into five groups, each of 10 rats as follows:
- Group 1: received normal saline orally and served as the normal control group.
- Group 2: received OVA.
- Group 3: received dexamethasone 1 h before OVA challenge till last challenge (after 24 days).
- Group 4: received nicorandil 1 h before OVA challenge till last challenge (after 24 days).
- Group5: received dexamethasone and nicorandil 1 h before OVA challenge till last challenge (after 24 days).
Animals were sensitized by intraperitoneal injection of 1 mg/kg OVA/100 mg aluminum hydroxide suspended in 1 ml normal saline for 3 consecutive days, followed by OVA inhalation (1%) for 15 min 1 day/week for 3 consecutive weeks using aerosolizing OVA solution in a special plastic cylindrical chamber (200 ml) introduced in an ultrasonic nebulizer .
The drugs were orally administrated 1 h before each OVA challenge and continued throughout the duration of experiment (24 days). Measurements were carried out 12 min after the last challenge (24 days).
At the end of the experiment, animals were kept on overnight fasting and were killed by decapitation. Lung sections were collected and then divided into two portions, one for histopathology where lung slices were cut in equal parts, fixed in 10% formaldehyde and embedded in paraffin; the 5 µm thick sections were stained with hematoxylin and eosin before observation under light microscope. The other part of the lung sections were homogenized and prepared for estimation of lung malondialdehyde (MDA), glutathione peroxidase (GPx), and transforming growth factor-β (TGF-β1).
Blood samples were collected from all studied groups and lifted for clotting at 37°C and then centrifuged for separation of serum for estimation of tumor growth factor-β (TGF-β1), tumor necrosis factor-α (TNF-α), interleukin (IL)-6. MDA and GPx levels in lung homogenates were assayed by spectrophotometry. TNF-α, IL, and TGF-β1 levels were determined by enzyme-linked immunosorbent assay.
Results were expressed by mean±SEM. Statistical significance of difference between groups was determined by analysis of variance followed by t test. A P value of less than 0.05 was considered significant.
| Results|| |
- Administration of ovabumin induced significant (P<0.05) increase in the lung tissue of MDA and TGF-β1 while it induced significant (P<0.05) decrease in GPx level when compared with the control group [Table 1] and [Table 2].
|Table 1 The levels of lung malondialdehyde, glutathione peroxidase, and tumor growth factor-β1 in different studied groups|
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|Table 2 Serum levels of tumor growth factor-β1 (pg/ml), tumor necrosis factor-α (pg/ml), and interleukin-6 (pg/ml) in different studied groups|
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- Administration of ovabumin induced significant (P<0.05) increase in serum levels of TGF-β1 (pg/ml), TNF-α, and IL-6 when compared with the control group.
- Administration of dexamethasone induced significant (P<0.05) decrease in lung tissue of MDA and TGF-β1 while it induced significant (P<0.05) increase in the GPx level when compared with the OVA group.
- Administration of dexamethasone induced significant decrease in serum levels of TGF-β1 (pg/ml), TNF-α, and IL-6 when compared with the OVA group.
- Administration of nicorandil alone or in combination with dexamethasone induced significant (P<0.05) decrease in the lung tissue of MDA and TGF-β1, while it induced significant (P<0.05) increase in GPx level when compared with the OVA group.
- Administration of nicorandil alone or in combination with dexamethasone induced significant decrease in serum levels of TGF-β1 (pg/ml), TNF-α, and IL-6 when compared with the ovalbumin group ([Figure 1],[Figure 2],[Figure 3],[Figure 4],[Figure 5],[Figure 6]).
|Figure 1 The levels of lung malondialdehyde (nmol/g lung tissue). *Significant when compared to control group (P<0.05). #Significant when compared to ovalbumin group (P<0.05).|
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|Figure 2 The levels of lung glutathione peroxidase (µmol/g lung tissue). *Significant when compared with the control group (P<0.05). #Significant when compared with the ovalbumin group (P<0.05).|
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|Figure 3 The levels of lung tumor growth factor-β1(pg/ml). *Significant when compared with the control group (P<0.05). #Significant when compared with the ovalbumin group (P<0.05).|
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|Figure 4 The serum levels of tumor growth factor-β1 (pg/ml). *Significant when compared with the control group (P<0.05). #Significant when compared with the ovalbumin group (P<0.05).|
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|Figure 5 The serum levels of tumor necrosis factor-α (pg/ml). *Significant when compared with the control group (P<0.05). #Significant when compared with the ovalbumin group (P<0.05).|
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|Figure 6 The serum levels of interleukin-6 (pg/ml). *Significant when compared with the control group (P<0.05). #Significant when compared with the ovalbumin group (P<0.05).|
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- Group 1 (normal; [Figure 7]): light microscopic study showed the normal histological picture of the lung tissues. It consisted of respiratory bronchioles, alveolar ducts sacs, and thin-walled alveoli. The alveoli were composed of a single layer of squamous epithelium. A thin layer of connective tissue and capillaries were present between alveoli.
|Figure 7 Control group of bronchial asthma model (hematoxylin and eosin, 400). Light microscopic study showed the normal histological picture of lung tissues. It consisted of respiratory bronchioles, alveolar ducts, sacs, and thin-walled alveoli. The alveoli were composed of a single layer of squamous epithelium. A thin layer of connective tissue and capillaries were present between alveoli.|
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- Group 2 (OVA; [Figure 8]): light microscopic study of the untreated asthma group showed perivascular and peribronchiolar eosinophilic infiltration and debris of eosinophils (Charcot–Leyden crystals). It also showed perivascular mast cells and lymphocytic infiltration. Moreover, the bronchial epithelial lining showed hypertrophic and hyperplastic changes and detached areas of the epithelial lining are present (cell debris). The bronchial lumens were bulged with mucus (Curschmann’s spirals).
|Figure 8 Ovalbumin group of bronchial asthma model (hematoxylin and eosin, 400) shows dense inflammatory cellular infiltration.|
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- Group 3 (dexamethasone; [Figure 9]): light microscopic study of the dexamethasone group showed the preservation of the normal histological structure of the lung tissues, with prevention of the histopathological changes induced by ova bronchial asthma model.
|Figure 9 Dexamethasone group of bronchial asthma (hematoxylin and eosin, 400) shows mild inflammatory cellular infiltration.|
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- Group 4 (niorandil; [Figure 10]): light microscopic study of the nicorandil group showed nearly normal lung tissues with mild peribronchiolar eosinophilic and lymphocytic infiltration.
|Figure 10 Nicorandil group of bronchial asthma model (hematoxylin and eosin, 400) shows mild inflammatory cellular infiltration.|
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- Group 5 (dexamethasone+nicorandil; [Figure 11]): light microscopic study of the combination of dexamethasone and nicorandil group showed nearly normal lung tissues with mild peribronchiolar eosinophilic and lymphocytic infiltration.
|Figure 11 Dexamethasone and nicorandil combination group of bronchial asthma model (hematoxylin and eosin, 400) shows mild inflammatory cellular infiltration.|
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| Discussion|| |
Oxidants–antioxidants balance is essential for the normal lung function. Both, an increased oxidant and/or decreased antioxidant may reverse the physiologic oxidant–antioxidant balance in favor of oxidants, leading to lung injury. A number of diseases involving the lung, such as COPD, emphysema, bronchiectasis, and bronchial asthma have been associated with a disturbance of these balances ,.
Currently, there is no direct effective therapy for asthma, only symptomatic treatment. Asthma cannot be completely healed or cured and thus needs continuous medical treatment. At present, inhaled corticosteroids and β2 agonists are used as the first line of treatment of asthma for reducing airway inflammation and bronchial constriction . Furthermore, relapse after therapy withdrawal is common  and the effects of these drugs are not always satisfactory in clinical practice because of local or systemic side effects . On the other hand, although coricosteroids improve asthma symptoms, they do not alter the progression of asthma or cure the disease . Thus, new or alternative approaches are being tried for asthma control.
In this study, administration of OVA induced significant decrease in the antioxidant system in rat lungs reflected by a decrease in GPx and an increase in MDA levels when compared with the control group. The amount of MDA is a measure of lipid peroxidation and its measure provides an estimate of free radical activity . This is in agreement with previous studies ,,,. They stated that erythrocyte SOD and Gpx enzyme activities were lowered in asthmatic children, either during acute attack or after 48 h of treatment. Contradictory to these results, another study  found that there was no significant correlation between severity of asthma and measurement of SOD and Gpx activities.
Regarding the effects of ovalbumin on inflammatory markers, it was found that OVA-induced significant increase in serum and tissue TGF-β1, serum IL-6, and TNF-α when compared with the control group. The pulmonary histological assay evidences that various degrees of inflammation appeared in all OVA-treated group. However, the asthmatic rats presented with more severe inflammation (inflammatory cell influx) than the treatment groups, and generally more serious inflammation was found in the OVA-treated group than the dexamethasone or nicorandil whether given alone or combined with the dexamethasone group. This in accordance with the results of Jang et al. , Dong et al. . They reported increased cytokine production and increased TGF-β1 levels in bronchoalveolar lavage fluids and lungs from OVA-sensitized and OVA-challenged mice. Similarly, Nadeem et al.  have reported increased lipid peroxidation products in patients with bronchial asthma. Lee  also reported increased serum and red blood cell thiobarbituric acid reactants in COPD patients.
The results of the present work has shown that dexamethasone produced a significant decrease in serum and tissue TGF-β1, serum IL-6, and TNF-α when compared with the ovalbumin group. Similar results were previously reported by Barnes  and Schwiebert et al. .
The anti-inflammatory effect of dexamethasone may be due to inhibition of the gene transcription of a cytosolic form of phospholipase A2 induced by cytokines  and inhibit the gene expression of cyclooxygenase-2, resulting in reduced formation of prostaglandins and thromboxanes . In contrast to the enzymes mentioned above, glucocorticoids have been shown to increase the expression of neutral endopeptidase ,, thereby potentially limiting neurogenic inflammatory responses. In accordance with these results, it was found that the expression of neutral endopeptidase on bronchial epithelial cells was higher in asthmatics treated with steroids compared with nonsteroid-treated asthmatics. Several studies have shown that cytokine-induced expression of eotaxin, IL-6, and IL-8 can be diminished by glucocorticoids in vitro ,,.
In this work, nicorandil administration whether alone or in combination with dexamethason significantly reduced serum levels of inflammatory markers (TGF-β1, TNF-α, and IL-6), and also significantly decreased lung malodialdehyde, lung TGF-β1 together with elevation of antioxidant activity presented by elevation of serum GPx level. This is in accordance with previous work  who reported that nicorandil significantly alleviated oxidative stress (as determined by lipid peroxides and reduced glutathione levels and total antioxidant capacity), as well as inflammatory markers (tumor necrosis factor-α and IL-1β), in the bronchoalveolar lavage fluid and testicular tissue on cyclophosphamide-induced lung and testicular toxicity in rats. Similar study has documented that nicorandil was effective in alleviating the decrement of heart rate and aortic blood flow and the state of mitochondrial oxidative stress induced by doxorubicin cardiotoxicity. Nicorandil also preserved phosphocreatine and adenine nucleotide contents by restoring mitochondrial oxidative phosphorylation capacity and creatine kinase activity. Moreover, nicorandil provided a significant cardioprotection through inhibition of apoptotic signaling pathway, DNA fragmentation, and mitochondrial ultrastructural changes . The mechanism by which nicorandil has been found to reduce oxidative stress may be through stimulating KATP channel opening, independent of its ability to donate NO ,. Another previous study  also reported the antioxidant activity of nicorandil as presented by the elevation of microsomal glutathione S-transferase activity after ischemia/reperfusion in isolated rat liver.
On the contrary, some authors  postulated that NO is the main nitrogen species produced in the lung and autoxidation of NO with oxygen results in the formation of nitrite, a substrate for eosinophil peroxidase and myeloperoxidase. Nitric oxide reacts with superoxide to form ONOO−, which can nitrate tyrosine residues and thus damage enzymes, and structural and functional proteins . Higher NO levels are associated with higher risk of asthma, asthma severity, and greater response to bronchodilator agents .
From the previous study, it could be concluded that nicorandil adminstration could ameliorate inflammatory process and oxidative stress induced by OVA whether administrated alone or combined with corticosteroids. Hence, we could use nicorandil with small doses of corticosteroids with the aim of reducing some of the side effects of corticosteroids in the long run.
Further studies are recommended to test the safety of nicorandil in humans and to calculate the minimum effective dose.
Many thanks to Professor Dr Karima El-Desoky, Department of Pathology, Faculty of Medicine, Tanta University, for her valuable help and for revising the pathology study.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11]
[Table 1], [Table 2]