Abstract
Montelukast is a highly selective leukotriene-receptor antagonist (LTRA). It is widely used in the treatment of bronchial asthma, primarily as an adjunct to corticosteroids. Reactive oxygen species (ROSs) play an important role in the pathogenesis of asthma and oxidative stress contributing to the initiation and worsening of inflammatory respiratory disorders, such as asthma. Antioxidant drugs may have a role in minimizing or preventing damage in asthmatic children. The aim of this study was to assess the antioxidant effect of montelukast on the production of free radicals in the whole blood and polymorphonuclear neutrophils (PMNs) in asthmatic children. A group of 48 (38 males and 10 females), apparently healthy asthmatic children were recruited with ages ranging between 6 and 14 years. In asthmatic children, base line (premedication) and post medication free radicals activity in the whole blood and polymorphonuclear neutrophils (PMNs) was determined by measuring chemiluminescence (CL) response through chemiluminescence luminometer. Free radical productions were significantly decreased in the whole blood, when stimulated with Phorbol Myristate Acetate (p < 0.04) and Opsonised Zymosan (p < 0.05). The free radicals were also significantly decreased in isolated polymorphonuclear neutrophils (PMNs) when stimulated with Opsonised Zymosan (p < 0.05) after the post medication treatment of montelukast in asthmatic children. Montelukast decreased the reactive oxygen species production, both in the whole blood as well as isolated PMNs in asthmatic children.
Keywords: Montelukast, Antioxidant, Free radicals production, Bronchial asthma
1. Introduction
Montelukast is highly selective antagonist of cysteinyl leukotriene (CysLT) receptors. It is commonly used in the treatment of bronchial asthma (Anonymous, 2004; Currie et al., 2005; Diamant and van der Molen, 2005; Riccioni et al., 2007; Al-Saadi, 2007). It has both anti-inflammatory as well as bronchodilator effects (Bousquet et al., 2009). Montelukast is an attractive drug, because it is available in an oral preparation form, which is easy to administer in children; and once-daily dosing is practically suitable to achieve greater compliance. It has a wide therapeutic window with low toxicity at therapeutic concentrations, appears safe and well tolerated by the patients (Cantrell and Farson-Collier, 2004). Montelukast has been found to reduce the symptoms of cough and wheeze, following bronchiolitis in infancy and has become popular in the treatment of bronchial asthma (Bisgaard et al., 2003).
The therapeutic effect of montelukast is achieved through antagonism of CysLT-mediated bronchoconstriction, increased vascular permeability and mucus secretion, following release of these mediators, mainly from monocytes/macrophages, eosinophils, mast cells and basophils. It also acts through the anti-inflammatory actions targeting type 2 helper CD4+ T-lymphocytes (Peters-Golden and Henderson, 2007). Unlike corticosteroids, montelukast has been reported to modulate airway remodelling in patients with chronic asthma (Muz et al., 2006; Henderson et al. 2006).
Bronchial asthma is the most common chronic inflammatory disease of childhood and its prevalence has substantially increased worldwide, particularly in pre-school children. It is associated with significant morbidity and economic burden (Harmanci, 2007). In bronchial asthma, mast cells, eosinophils and lymphocytes are involved in the expression of an inflammatory process in response to triggering agents in susceptible individuals. It is well-known that oxygen-derived free radicals contribute to the inflammation in asthma. When PMNs are stimulated in vivo, their phoslipase is activated and leukotrienes are liberated through the lipoxygenase pathway. The leukotrienes contribute to oxidative stress and the initiation and worsening of asthma. They actually produce typical presentation of the late phase of an asthma attack. The pharmacological indications of Montelukast have been well established, but its clinical significance is still lacking in certain areas, such as its role in free radicals production. Therefore, the aim of the present study was to investigate the possible antioxidant effect of montelukast in asthmatic children, using in vitro chemiluminescence technique in the whole blood and isolated ploymorphonuclear neutrophils.
2. Subjects and methods
The present study was conducted in the Departments of Pediatrics and Physiology, College of Medicine, King Saud University, Riyadh, Saudi Arabia from the year 2006–2008. The Ethics Committee, College of Medicine Research Centre (CMRC) approved the study.
2.1. Subjects
In this study, a group of 48 apparently healthy, volunteers, asthmatic children (38 males and 10 females) with ages ranging between 6 and 14 years, were recruited from the various hospitals in Riyadh. The mean duration of the disease was 4.55 ± 0.44 years. The participating children or their parents completed a questionnaire, which included anthropometric data and a consent form.
2.2. Exclusion criteria
Children with gross anemia, known history of diabetes mellitus, autoimmune diseases and malignancy were excluded. Children with current or previous history of cigarette smoking were also excluded from the study.
2.3. Methods
Blood (5–6 ml) was collected from each child by venipuncture in a disposable syringe. Blood was heparinized (10 IU/ml Fischer Scientific Co., NJ) and the tubes containing this heparanized blood were immediately kept in ice, to prevent any reactions to the time of measurement of free radicals activity by measuring the chemiluminescence (CL) response. Each specimen bottle was labeled with the subject identification code number.
2.4. Chemiluminescence assay
LKB-Wallac 125l Luminometer is a bench top, microcomputer controlled luminescence-measuring instrument capable of providing instantaneous monitoring of reactive oxygen species events. This Luminometer is attached to a display unit and printer. Disposable polystyrene cuvettes suitable for the Luminometer and micropipettes with disposable tips for dispensing 100–1000 μ1 volumes were used.
2.5. Reagents: preparation of luminol
Liminol (LKB-Wallac 1234–216) was dissolved in dimethyl sulfoxide (DMSO) to give a concentration of 1.77 mg/ml. It was further diluted in phosphate-buffered saline (PBS) to 17.7 μg/ml prior to use.
2.6. Preparation of phorbol myristate acetate (PMA solution)
PMA was dissolved in DMSO to give a stock solution of 2 mg/ml. The solution was stored at 20 °C until used. It was further diluted with phosphate buttered saline (PBS) to 20 μg/ml, prior to use.
2.7. Phosphate-buffered saline solution (PBS)
It was made up in distilled water according to the following composition NaCl 0.14 M, KCL 2.7 mM, Na2HPO2 mM, KH2PO4 1.5 mM, CaCl2 0.9 mM, and MgCl2 0.49 mM.
2.8. Polymorphonuclear neutrophils (PMN) separation
PMNs were separated by using Neutrophils isolation medium (NIM) obtained from Cardinal Associates Inc, Santa Fe, NM 87502. In a 15 ml tube, 5–6 ml of heparinized blood was layered over 4 ml of NIM and then centrifuged at 400g for 30 min, at room temperature. After centrifugation, the blood was separated into layers according to the weight of the cells. Carefully, the leukocyte-rich plasma (appears as pinkish ring) was removed with a Pasteur pipette and transferred to a 15 ml conical centrifuge tube. The tube was filled with PBS and centrifuged at 350g for 10 min in a Heraeus (Model GmbH, Osterode). The residual erythrocytes were lysed in 2 ml of lysing buffer (E-lyse) obtained from Cardinal Associate Inc. Santa Fe, NM 87502, which was vortexed to resuspend the pellets and then centrifuged at 250g for 10 min. The supernatant was discarded and the sediment was suspended in 1 Ml of 5% FCS. The cells were counted and adjusted to 5 million/ml.
2.9. Isolated PMNS assay
The cuvette contents were mixed gently and conveyed to the measurement position. The light emission was recorded in mV. The assay temperature was kept constant at 37.0 °C. Each sample was measured over a period of 30 min; the results were plotted using a computer in a graph with Y-axis representing the light intensity in mV and X-axis representing the time in minutes.
2.10. Antileukotriene (Montelukast) in vitro-study
Montelukast was purchased from Sigma Chemical Company, St. Louis MO, USA and the drug was supplied as a pure and authentic powder. To each 2 mg of the 6 μl of 1 N, sodium hydroxide was added until the mixture appeared pasty. The 100 μl of polyethylene glycol (400 MWT) were added. This paste-like material was warmed at low temperature, until a clear solution was obtained. This was made up to the required volume of 2 ml by adding PBS (pH 7.4). The PBS was added in increasing amount, to avoid precipitation of the compound. This stock solution was further diluted to the required concentration (range 1.25–60 μg/ml).
2.11. Effects of different concentrations on ROS generation from PMNS
The effect of Montelukast on the generation of ROS, as assessed by CL was determined by addition of different concentrations of the drug to isolated PMNs that were stimulated with PMA.
2.12. Effect of incubation time on ROS generation
The effect of Montelukast (5 and 10 μg) on ROS generation was tested at different time intervals: 0, 10, 30, and 60 min after incubation at 37 °C.
2.13. Reversibility of the effect of Montelukast
In order to investigate whether Montelukast would have a permanent effect on PMNs or not, two different concentrations of 30 and 60 μg were incubated for 45 min with isolated PMNs and washed thereafter several times with PBS. The CL of unwashed and washed samples in the presence of Montelukast was recorded.
2.14. Statistical analysis
The data were analyzed by using a SPSS Pc+ version 16.0 Statistical program. The descriptive statistics, median, range and inter quartile range values were used to describe the outcome variables, due to the skewed distribution of outcome variables. The comparison of pre and post values of outcome variables was carried out by applying a non parametric Wilcoxon Signed Ranks Test. A p-value of <0.05 was considered as statistically significant.
3. Results
In this study on asthmatic children, base line (premedication) and post medication free radicals activity in the whole blood and polymorphonuclear neutrophils (PMNs) was determined by measuring chemiluminescence (CL) response through chemiluminescence luminometer.
Table 1 shows the effects of Montelukast on free radical production in the whole blood, (WB) stimulated with phorbol myristate acetate (PMA) and opsonised zymosan (OPZ) in asthmatic children. The median, range, and Interquartile range values were obtained from the whole blood in asthmatic children. There was a significant decline in free radical production in the whole blood (WB) stimulated with phorbol myristate acetate (PMA) (p < 0.04) and opsonised zymosan (OPZ) (p < 0.05) in asthmatic children before and after the treatment with montelukast.
Table 1.
Effects of Montelukast on free radical production in the whole blood (WB), stimulated with PMA and OPZ in asthmatic children.
| Parameters | Asthmatic children premedication (n = 48) | Asthmatic children post medication (n = 48) | p-Value |
|---|---|---|---|
| PMA(CL-mV) | |||
| Median | 14.40 | 10.15 | 0.04 |
| Range | 47.30 | 31.69 | |
| Interquartile range | 14.20 | 13.15 | |
| OPZ(CL-mV) | |||
| Median | 24 | 21.75 | 0.05 |
| Range | 100.60 | 213.80 | |
| Interquartile range | 39.92 | 22.25 | |
CL = Chemiluminescence response, PMNs = Polymorphonuclear Neutrophils; OPZ = Opsonised Zymosan; PMA = Phorbol Myristate acetate. PMN concentration = 5 × 106 cells/ml; OPZ concentration = 1.25 mg/ml; Luminol concentration = 10−4 M. Values are expressed as median, range, and interquartile range.
Table 2 demonstrates the effects of montelukast on free radical production in isolated Polymorphonuclear neutrophils (PMNs), stimulated with phorbol myristate acetate (PMA) and opsonised zymosan (OPZ) in asthmatic children. The median, range, and interquartile range values were measured before and after the medication of montelukast. There was a significant decrease in free radical productions in isolated PMNs when stimulated with OPZ (p < 0.043) in asthmatic children. However, no significant difference was achieved when stimulated with PMA (p = 0.08).
Table 2.
Effects of Montelukast on free radical production in isolated polymorphonuclear neutrophils PMNs, stimulated with PMA and OPZ in asthmatic children.
| Parameters | Asthmatic children premedication (n = 48) | Asthmatic children post medication (n = 48) | p-Value |
|---|---|---|---|
| PMA (CL-mV) | |||
| Median | 398.55 | 245.35 | 0.08 |
| Range | 1494 | 1363 | |
| Interquartile range | 280.80 | 244.30 | |
| OPZ (CL-mV) | |||
| Median | 1517.45 | 1171 | 0.04 |
| Range | 3551.70 | 4002.60 | |
| Interquartile range | 1144.37 | 1913.20 | |
CL = Chemiluminescence response, PMNs = Polymorphonuclear Neutrophils; OPZ = Opsonised Zymosan; PMA = Phorbol Myristate acetate. PMN concentration = 5 × 106 cells/ml; OPZ concentration = 1.25 mg/ml; Luminol concentration = 10−4 M. Values are expressed as median, range, and interquartile range.
4. Discussion
Montelukast is a selective and orally active leukotriene receptor antagonist, that inhibits the cysteinyl leukotriene CysLT1 receptor. It appears to be useful for the preschool age children, when there is coexisting allergic rhinitis (Van Adelsberg et al., 2003), and may also reduce the symptoms, when used as a short course in intermittent asthma. It has a very narrow spectrum of action in comparison to the broad anti-inflammatory action of the commonly used inhaled corticosteroids. It blocks the action of cysteinyl leukotrienes, which catalyze the inflammatory cascade from eosinophils, mast cells and alveolar macrophages (Bisgaard et al., 2005). This reduces the main characteristics of asthma, such as airflow obstruction, mucus hypersecretion, mucosal oedema and desquamation, bronchoconstriction, bronchial hyperresponsiveness and eosinophil accumulation (Smith, 2007). Many drugs are used in the treatment of asthma in children, but in the present study, the objective was to find out a suitable drug which can also reduce the reactive oxygen species (ROS) production in asthmatic children. This is because the ROS play an important role in the pathogenesis of asthma and oxidative stress contributes to the initiation and worsening of inflammatory respiratory disorders, which include asthma. According to an earlier study, antioxidant drugs may have a role in reducing or preventing damage in asthmatic patients (Al-Zamil et al., 2005).
The free radicals and reactive oxygen molecules are generated by activated neutrophils, monocytes and other cells during inflammatory processes. In acute inflammation, activated polymorphonuclear leukocytes release lysosomal hydrolytic enzymes, lipid mediators, and reactive oxygen species that may damage the surrounding viable tissues (Noiri et al., 2000). Tugtepe et al. (2007) demonstrated that montelukast attenuated neutrophil recruitment and promoted the resolution of inflammation by antagonizing the effects of leukotrienes, which are potent stimuli for leukocyte infiltration. It has been shown that montelukast acts through the inhibition of neutrophils in several organs targeted by various inflammatory challenges (Sener et al., 2006). The results of the present study suggest inhibitory effect of the montelukast on reactive oxygen species (ROS) production in the whole blood (WB) and isolated PMNs, when stimulated with phorbol myristate acetate (PMA) and opsonised zymosan (OPZ) in asthmatic children.
Biber et al. (2009) reported that montelukast has beneficial effects against the traumatic brain injury induced oxidative stress in Sprague Dawley rats, suggesting that montelukast, not only decreases the reactive oxygen species in respiratory system, but it is also effective against the traumatic brain injury induced oxidative stress.
Anderson et al. (2009) demonstrated the effects of montelukast on the generation of ROS, using the lucigenin and luminal enhanced CL procedures. They showed that, treatment of the cells with montelukast resulted in a dose-related inhibition of the generation of ROS, which was evident in both procedures and which achieved statistical significance at the concentrations of 0.5 μmol/L (lucigenin, P < 0.001) or 1 μmol/L−1 (luminol, P < 0.01). Moreover, they found a maximal inhibition at 2 μmol/L−1 montelukast, resulting in 70% and 60% inhibition of the generation of ROS with lucigenin and luminal enhanced CL procedures, respectively.
In the present study, significant inhibition of ROS production was observed at the lowest concentration of the drug used without incubation. In this study, montelukast was associated with more inhibition of PMA-stimulated ROS production in the whole blood compared with that induced by OPZ as shown in Table 1. Montelukast was also associated with inhibition of OPZ-stimulated ROS production in isolated PMNs with that induced by PMA. This finding agrees with the earlier reports which concluded that, depending on the receptor or combination of receptors, activated different signal transduction pathways might be involved in respiratory burst (Della Bianca et al., 1986). In addition, Raulf and Konig (1988) found that stimulation of human PMNs with OPZ resulted in time and dose dependent release of LTB4 and LTC4. On the other hand, priming of PMNs with PMA has been shown to increase 5-1ipoxygenase kinase activity by translocation of 5-1ipoxygenase to the nucleus and by increasing its capacity for phosphorylation. Therefore, signal transduction pathways involved in the stimulation of PMA receptors will result in high 5-1ipoxygenase activity (Nagarajan et al., 2000). In the present study, free radical productions were significantly decreased in the whole blood, when stimulated with PMA (p < 0.04), OPZ (p < 0.05), and in isolated PMNs when stimulated with OPZ (p < 0.05) after post medication treatment of montelukast in asthmatic children. However, no statistically significant inhibition of free radical productions was observed in isolated PMNS when stimulated with PMA, after post medication treatment of montelukast in asthmatic children. This difference could be due to the increase in complement receptor type 3, which is involved in clearing OPZ on PMNs in asthmatic patients. Based on the findings of the present study, we speculate that the activation of PMNs in asthmatic children results in increased generation of LTs, which in turn, acts on PMN cys LT1R to stimulate the release of ROS. The results of this study also suggest that montelukast interferes with this autocrine activation of PMNs by blocking the cys LT receptors, thereby inhibiting ROS production.
The results of this study suggest that LT receptor antagonists represent a novel therapeutic approach with dual beneficial effects, as an antioxidant and an anti-inflammatory drug in the management of pediatric asthma. Furthermore, our findings might explain the mechanism of action of cys LTs in producing tissue inflammation, suggesting that LT receptor antagonists in addition to their use as anti-inflammatory drugs may also be useful as antioxidants.
The present study had some limitations, including the small sample size of participating asthmatic children, and the gender disproportion in the study subjects (38 males vs 10 males). The severity of asthma was not considered in this study. It is possible that patients with different severity of asthma react differently to montelukast. Furthermore, this was an in vitro study, hence it is suggested that studies with larger sample size are needed for further in depth evaluation of the role of montelukast in asthmatic children.
5. Conclusions
Reactive oxygen species (ROSs) play an important role in the pathogenesis of asthma, and oxidative stress contributes to the initiation and worsening of inflammatory respiratory disorders. Montelukast was found to decrease the reactive oxygen species production, both in the whole blood as well as the isolated PMNs, when stimulated with PMA and OPZ in asthmatic children. It is therefore suggested that montelukast has an additional role for the inhibition of ROS production in asthmatic children.
6. Conflict of interest
No conflict of interest.
Acknowledgements
This work was supported by the College of Medicine Research Centre (CMRC), King Saud University, Riyadh, KSA (Grant No. 06-526). We also thank Mr. Casimero Victoria, Neutrophil Function Laboratory, Department of Physiology, College of Medicine, King Saud University for technical assistance.
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