Cysteinyl Leukotriene Receptor Antagonist Montelukast Research Articles

Exploring the neuroprotective effects of montelukast on brain inflammation and metabolism in a rat model of quinolinic acid-induced striatal neurotoxicity

BackgroundOne intrastriatal administration of quinolinic acid (QA) in rats induces a lesion with features resembling those observed in Huntington’s disease. Our aim is to evaluate the effects of the cysteinyl leukotriene receptor antagonist montelukast (MLK), which exhibited neuroprotection in different preclinical models of neurodegeneration, on QA-induced neuroinflammation and regional metabolic functions.MethodsThe right and left striatum of Sprague Dawley and athymic nude rats were injected with QA and vehicle (VEH), respectively. Starting from the day before QA injection, animals were treated with 1 or 10 mg/kg of MLK or VEH for 14 days. At 14 and 30 days post-lesion, animals were monitored with magnetic resonance imaging (MRI) and positron emission tomography (PET) using [18F]-VC701, a translocator protein (TSPO)-specific radiotracer. Striatal neuroinflammatory response was measured post-mortem in rats treated with 1 mg/kg of MLK by immunofluorescence. Rats treated with 10 mg/kg of MLK also underwent a [18F]-FDG PET study at baseline and 4 months after lesion. [18F]-FDG PET data were then used to assess metabolic connectivity between brain regions by applying a covariance analysis method.ResultsMLK treatment was not able to reduce the QA-induced increase in striatal TSPO PET signal and MRI lesion volume, where we only detected a trend towards reduction in animals treated with 10 mg/kg of MLK. Post-mortem immunofluorescence analysis revealed that MLK attenuated the increase in striatal markers of astrogliosis and activated microglia in the lesioned hemisphere. We also found a significant increase in a marker of anti-inflammatory activity (MannR) and a trend towards reduction in a marker of pro-inflammatory activity (iNOS) in the lesioned striatum of MLK—compared to VEH-treated rats. [18F]-FDG uptake was significantly reduced in the striatum and ipsilesional cortical regions of VEH-treated rats at 4 months after lesion. MLK administration preserved glucose metabolism in these cortical regions, but not in the striatum. Finally, MLK was able to counteract changes in metabolic connectivity and measures of network topology induced by QA, in both lesioned and non-lesioned hemispheres.ConclusionsOverall, MLK treatment produced a significant neuroprotective effect by reducing neuroinflammation assessed by immunofluorescence and preserving regional brain metabolism and metabolic connectivity from QA-induced neurotoxicity in cortical and subcortical regions.

Montelukast Has no Impact on the Systemic Production of TGFβ-1 in Patients with Nasal Polyposis Associated with Aspirin Intolerance.

Introduction Nasal polyposis is a disease characterized by a mechanical dysfunction of the nasal mucosa, closely related to the unique makeup of its extracellular matrix, which develops as the result of an anomalous tissue remodeling process. Transforming growth factor beta 1 (TGF-β1) is reduced not only in the nasal polypoid tissue, but also in the plasma of aspirin-intolerant patients. These patients exhibit an imbalance in the production of eicosanoids characterized by an increase in leukotrienes. Thus, it is important that the relationship between the production of leukotrienes and TGF-β1 be assessed. Objective To evaluate the effects of the cysteinyl leukotriene (CysLT) receptor antagonist montelukast on the systemic production of TGF-β1 in patients with nasal polyposis, with or without concomitant aspirin intolerance. Methods The sample comprised 48 individuals with diagnosis of nasal polyposis and 15 healthy controls for comparison of the baseline TGF-β1 levels in the peripheral blood and after treatment with CysLT receptor antagonist montelukast in the nasal-polyposis group. Results There was no difference in the change in TGF-β1 levels after the treatment with montelukast in the subgroup of patients with polyposis and asthma ( p = 0.82) and in the subgroup with polyposis, asthma, and aspirin intolerance ( p = 0.51). Conclusion we found no impact of the therapy with a leukotriene receptor blocker on the production of TGF-β1, making the antileukotriene therapy a highly questionable choice for the treatment of nasal polyposis, particularly from the standpoint of seeking to modify the remodeling process in this disease.

Montelukast Potentiates the Antiinflammatory Effect of NSAIDs in the Rat Paw Formalin Model and Simultaneously Minimizes the Risk of Gastric Damage

Although the cysteinyl leukotriene receptor antagonist montelukast has been recognized for its antiinflammatory action, little information is available on whether this effect would be intensified if montelukast is co‐administered with nonsteroidal antiinflammatory drugs (NSAIDs). Here, we tested the hypothesis that simultaneous exposure to montelukast and NSAIDs elicits more efficacious control of histopathological and inflammatory signals in the rat paw formalin model. We also determined whether montelukast could improve gastric damage caused by NSAIDs and associated inflammatory insults. The individual treatment of rats with montelukast (20 mg/kg), diclofenac (nonselective COX1/COX2 inhibitor, 10 mg/kg), or celecoxib (selective COX2 inhibitor, 10 mg/kg) significantly reduced the formalin‐induced increases in (i) paw edema, (ii) necrotic debris and keratinized stratified squamous epithelium, (iii) paw protein expressions of iNOS and COX2, and (iv) serum IL‐6 and LTB4. These favorable histopathological and molecular effects were accentuated in rats treated with montelukast plus diclofenac or celecoxib. Alternatively, montelukast reduced the diclofenac‐evoked gastric damage (lesions and hyperemia) and rises in gastric TNFα levels, but it failed to alter the concomitant reductions in gastric COX1 expression and PGE2 content. Unlike diclofenac, normal gastric mucosal and COX1/PGE2 patterns were observed in celecoxib‐treated animals. Overall, the current data provide evidence that montelukast boosts the antiinflammatory action of NSAIDs while diminishing the potential of gastric damage and inflammation.

Mechanisms underlying the protective effect of leukotriene receptor antagonist montelukast against doxorubicin induced testicular injury in rats

The obligatory use of cytotoxic drugs to face the malignant tumors results in survivors that suffer from long term health problems. Fertility problems, especially in young boys, exert one of the major consequences of chemotherapy treatment that needs resolution. We investigate the potential effect of the cysteinyl leukotriene receptor antagonist montelukast on doxorubicin-induced testicular damage. Five groups of adult Wistar male rats were subjected to the following treatment; vehicle for the control group, montelukast (20 mg/kg orally daily for 10 days) for the drug control, doxorubicin (12 mg/kg intraperitoneal injection once at 5th day) for the toxic group, montelukast at 10 mg/kg + doxorubicin, montelukast at 20 mg/kg + doxorubicin. The period of the experiment was 10 days administration of montelukast, while doxorubicin was injected at the 5th day. Results of serum testosterone, testicular lipid peroxidation, antioxidant status, and histopathology revealed protection of montelukast against doxorubicin-induced testicular damage. The pro-apoptotic caspase 3 and the pro-inflammatory tumor necrosis factor-alpha were examined immunohistochemically and showed a significant decrease with montelukast treatment as compared to doxorubicin group. Doxorubicin increased gene expression of matrix metalloproteinase 9 and decreased peroxisome proliferator activated receptor gamma. Montelukast treatment restored their expressions to normal values.In conclusion, montelukast administration can ameliorate the testicular damage induced by doxorubicin based on its anti-inflammatory, antioxidant and anti-apoptotic effects as well as by of modulation of important genes expression.

Protective effect of cysteinyl leukotriene receptor antagonist montelukast in bleomycin-induced pulmonary fibrosis.

This study aims to investigate the early- and late-term effects of pharmacological inhibition of cysteinyl leukotriene activity by using montelukast in bleomycin-induced inflammatory and oxidative lung injury in an animal model. The study included 48 male Wistar albino rats (weighing 250 g to 300 g). Rats were administered intratracheal bleomycin or saline and assigned into groups to receive montelukast or saline. Bronchoalveolar lavage fluid and lung tissue samples were collected four and 15 days after bleomycin administration. Bleomycin resulted in significant increases in tumor necrosis factor-alpha levels (4.0±1.4 pg/mL in controls vs. 44.1±14.5 pg/mL in early-term vs. 30.3±5.7 pg/mL in late-term, p<0.001 and p<0.001, respectively), transforming growth factor beta 1 levels (28.6±6.6 pg/mL vs. 82.3±14.1 pg/mL in early-term vs. 60.1±2.9 pg/mL in late-term, p<0.001 and p<0.001, respectively), and fibrosis score (1.85±0.89 in early-term vs. 5.60±1.14 in late-term, p<0.001 and p<0.01, respectively). In bleomycin exposed rats, collagen content increased only in the late-term (15.3±3.0 ?g/mg in controls vs. 29.6±9.1 ?g/mg in late-term, p<0.001). Montelukast treatment reversed all these biochemical indices as well as histopathological alterations induced by bleomycin. Montelukast attenuates bleomycin-induced inflammatory and oxidative lung injury and prevents lung collagen deposition and fibrotic response. Thus, cysteinyl leukotriene receptor antagonists might be regarded as new therapeutic agents for idiopathic pulmonary fibrosis.

328: Cysteinyl leukotriene receptor antagonist montelukast for the management of spontaneous preterm labour - a pilot randomized controlled trial

Inflammation play a major role in preterm birth. Cysteinyl leukotrienes (cys-LTs) are potent mediators of inflammation derived from arachidonic acid. Montelukast, a cys-LTs receptor antagonist and anti-inflammatory agent, is a consistent tocolytic in vitro (Corriveau 2014). In this study, we aimed to prepare a randomised control trial (RCT) to evaluate the impact of Montelukast on the rate of spontaneous preterm birth.

Cysteinyl leukotriene receptor antagonist montelukast ameliorates acute lung injury following haemorrhagic shock in rats†

The aim of this study was to assess the possible protective effect of montelukast against haemorrhagic shock-induced acute lung injury by interfering with inflammatory and oxidative pathways. Acute lung injury following haemorrhagic shock/resuscitation is an important contributor to late morbidity and mortality in trauma patients. Haemorrhagic shock (HS), followed by resuscitation, is considered to be an insult that frequently induces systemic inflammatory response syndrome and oxidative stress, resulting in multiple-organ dysfunction syndrome, including microvascular changes and microscopic damage termed acute lung paraynchymal injury. Montelukast is a cysteinyl leukotriene receptor antagonist that exerts an anti-inflammatory and antioxidant influence. Eighteen adult albino rats were assigned to three groups of six. In Group I, the 'sham' group, rats underwent all the surgical procedures but neither haemorrhagic shock nor resuscitation was carried out. Group II--the 'HS' induced, untreated group--was the control and underwent HS for one hour before being resuscitated with Ringer's lactate for one hour. Group III--the 'montelukast' group--underwent HS and treatment with montelukast (7 mg/kg i.p. injection) 30 min before the induction of HS, with the same dose repeated just before the reperfusion period. At the end of the experiment, two hours after completion of resuscitation, blood samples were collected for measurement of serum tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). The trachea was then isolated and bronchoalveolar lavage was carried out for measurement of leukotriene B(4) (LTB(4)), leukotriene C(4) (LTC(4)) and total protein. The lungs were harvested and the left lung was homogenized for measurement of malondialdehyde (MDA) and reduced glutathione (GSH) and the right lung was fixed in 10% formalin for histological examination. Montelukast treatment (Group III) significantly reduced the total lung injury score, compared with the HS group (Group II) (P < 0.05). Montelukast also significantly decreased serum TNF-α and IL-6; lung MDA; bronchoalveolar lavage fluid (BALF) LTB(4), LTC(4) & total protein compared with the HS group (P < 0.05). Montelukast treatment significantly inhibited decrease in the lung GSH levels, compared with the HS group (P < 0.05). The results of the present study reveal that montelukast may ameliorate lung injury in shocked rats by interfering with inflammatory and oxidative pathways, implicating the role of leukotrienes in the pathogenesis of haemorrhagic shock-induced lung inflammation.

Montelukast, A Selective Cysteinyl Leukotriene Receptor 1 Antagonist, Reduces Cerulein-Induced Pancreatic Injury in Rats

This study was designed to evaluate the protective effect of the cysteinyl leukotriene receptor antagonist montelukast against pancreatic injury during acute pancreatitis. Acute pancreatitis was induced in rats by 20-μg/kg (intraperitoneal) cerulein given at 1-hour intervals within 4 hours. Montelukast was administered intraperitoneally at a dose of 10 mg/kg 15 minutes before the first cerulein injection. Six hours after the cerulein or saline injections, the animals were killed by decapitation. Blood samples were collected to analyze amylase, lipase, and the proinflammatory cytokines tumor necrosis factor α and interleukin 1β. Pancreas tissues were taken for the determination of tissue glutathione and malondialdehyde levels and Na,K-adenosine triphosphatase and myeloperoxidase activities. The extent of tissue injury was analyzed microscopically. Acute pancreatitis caused significant decreases in tissue glutathione level and Na,K-adenosine triphosphatase activity, which were accompanied with significant increases in the pancreatic malondialdehyde level, myeloperoxidase activity, and plasma cytokine level. On the other hand, montelukast treatment reversed all these biochemical indices and histopathological alterations that were induced by cerulein. These results suggest that cysteinyl leukotrienes may be involved in the pathogenesis of acute pancreatitis and that the cysteinyl leukotriene receptor antagonist, montelukast, might be of therapeutic value for treatment of acute pancreatitis.

Pharmacological Characterization of Itch-Associated Response Induced by Repeated Application of Oxazolone in Mice

We investigated pharmacological characteristics of the itch-associated response to chronic dermatitis induced by 4-ethoxymethylene-2-phenyl-2-oxazolin-5-one (oxazolone) repeated application in mice. Application of an oxazolone challenge to mice with oxazolone-induced chronic dermatitis evoked severe and transient scratching behavior for up to 1h. Thereafter, mild and continuous scratching behavior was observed for at least 8 h. Both severe and continuous scratching behaviors were suppressed by the opioid-receptor antagonist naltrexone, but not by the H1 histamine–receptor antagonist fexofenadine, 5-hydroxytryptamine-2 (5-HT2)–receptor antagonist methysergide, NK1-receptor antagonist LY303870, cyclooxygenase inhibitor indomethacin, or the platelet-activating factor–receptor antagonist YM264. The severe scratching behavior was suppressed by the 5-lipoxygenase inhibitor zileuton and leukotriene B4–receptor antagonist ONO-4057, but not by the cysteinyl leukotriene–receptor antagonist montelukast. The continuous scratching behavior was suppressed by pretreatment with the non-selective muscarinic acetylcholine–receptor antagonist atropine and M3 muscarinic acetylcholine–receptor antagonist darifenacin. These results suggest that leukotriene B4 receptor and M3 muscarinic acetylcholine receptor are involved in the itch-associated response induced by repeated application of oxazolone in mice.

Cysteinyl-leukotriene receptor antagonist montelukast decreases blood–brain barrier permeability but does not prevent oedema formation in traumatic brain injury

Introduction: Traumatic brain injury is highly associated with the over-production of reactive oxygen species. The aim of this study was to investigate the putative neuroprotective effect of montelukast, a cysteinyl-leukotriene receptor antagonist, in a rat model of traumatic brain injury (TBI).Methods: Sprague Dawley rats were subjected to TBI with a weight-drop device using 300 g-1 m weight-height impact. The groups were: control (saline), montelukast (10 mg kg −1 per day, ip), trauma and trauma + montelukast. Two days post-trauma, neurological examination scores were measured and animals were decapitated and the brain tissues were taken for the histologic and biochemical [malondialdehyde (MDA)—an index for lipid peroxidation, reduced glutathione (GSH), myeloperoxidase (MPO)—an index for neutrophil infiltration and Na +/K +-ATPase activity] evaluations. Brain oedema and blood–brain barrier (BBB) permeability were also evaluated.Results: The neurological examination scores mildly increased in trauma groups at 48 hours. Although the scores were decreased in the montelukast treated group, they were still significantly higher than the control. The trauma caused a significant increase in brain water content and Evans blue (EB) extravasation. Montelukast treatment reduced BBB permeability. It also decreased lipid peroxidation and MPO activity.Conclusion: The present study suggests that montelukast may have beneficial effects against TBI-induced oxidative stress of the brain.

The effect of montelukast on soluble interleukin-2 receptor and tumor necrosis factor α in pediatric asthma

Proinflammatory cytokines such as tumor necrosis factor (TNF) alpha and soluble interleukin 2 receptor (sIL-2R) are very important mediators in induction of inflammatory response in lung. The aim of this study was to investigate anti-inflammatory response of cysteinyl leukotriene receptor antagonist montelukast on macrophage and T-cell activation by sIL-2R and TNF-alpha in mild atopic asthmatic children. Fifteen children with mild-to-moderate atopic asthma and 15 nonatopic children as control, enrolled in the study. Asthmatic children were treated with montelukast, 5-mg tablets, for 1 month. Lung function test forced expiratory volume in 1 second (FEV1) was performed before and after treatment. Serum TNF-alpha, sIL-2R, and eosinophil cationic protein levels were determined in the control group and in asthmatic children before and after treatment. The mean eosinophil cationic protein value was significantly decreased (33.1 +/- 14.8 and 22.2 +/- 12.1; p < 0.05) and FEV1 was significantly increased (86.9 +/- 20.9 and 102.1 +/- 12.7; p < 0.05) after 1 month treatment with montelukast. The mean serum IL-2R levels were significantly higher in the before treatment group than in the after treatment group (1061.9 +/- 491 and 794 +/- 230.9; p < 0.05) or in control subjects (581.1 +/- 123; p < 0.01). The mean serum TNF-alpha level was higher in the before treatment group than in the after treatment group and control group (7.30 +/- 3.93, 5.20 +/- 1.46, and 4.95 +/- 1.27; p < 0.05). There was a significant correlation between TNF-alpha and sIL-2R in patients before montelukast treatment (r = 0.674; p < 0.01). This study indicates that montelukast improves clinical parameters and shows anti-inflammatory response by decreasing serum sIL-2R and TNF-alpha levels.

Anti-inflammatory effects of montelukast in mild cystic fibrosis

Immune-mediated inflammation contributes to progressive pulmonary damage in cystic fibrosis (CF). Sputum cysteinyl leukotriene levels, eosinophil cationic protein (ECP), and interleukin-8 (IL-8) are significantly related to disease severity. The aim of this study was to evaluate the anti-inflammatory and clinical effects of the cysteinyl leukotriene receptor antagonist montelukast in children with CF. A double-blind, randomized, crossover design was used. Patients received montelukast (6 to < or = 14 years, 5 mg; > 14 years, 10 mg) or placebo as a once-daily tablet for 21 days and then, after a washout period of at least 4 weeks, crossed over to receive the alternative treatment. Blood and native nasal fluid were taken on days 1 and 21 of each treatment block, and WBC count, ECP, and IL-8 were analyzed using a chemiluminescent immunometric assay. Sixteen CF patients (10 boys, 6 girls; age, 5 to 18 years, median 9.5 years) completed the trial. There was a significant (P < or = 0.02) reduction of serum ECP (median reduction: montelukast 7.7 microg/L vs placebo 0.15 microg/L) and eosinophils (P < or = 0.027; median reduction: montelukast 85/microL vs placebo 0/microL). There was no significant change in nasal ECP, IL-8, or serum IL-8 after a 21-day course of montelukast. Clinical symptom scores did not change significantly. Montelukast reduces eosinophilic inflammation in CF patients. Multicenter trials providing more patients to create more data to prove the hypothesis that montelukast is an effective tool to cut down disease severity in CF patients are needed.