montelukast and Seizures

Cysteinyl leukotrienes (CysLTs) have been implicated in seizures and kindling; however, the effect of CysLT receptor antagonists on seizure frequency in kindled animals and changes in CysLT receptor expression after pentylenetetrazol (PTZ)-induced kindling have not been investigated. In this study, we evaluated whether the CysLT1 inverse agonist montelukast, and a classical anticonvulsant, phenobarbital, were able to reduce seizures in PTZ-kindled mice and alter CysLT receptor expression. Montelukast (10 mg/kg, sc) and phenobarbital (20 mg/kg, sc) increased the latency to generalized seizures in kindled mice. Montelukast increased CysLT1 immunoreactivity only in non-kindled, PTZ-challenged mice. Interestingly, PTZ challenge decreased CysLT2 immunoreactivity only in kindled mice. CysLT1 antagonists appear to emerge as a promising adjunctive treatment for refractory seizures. Nevertheless, additional studies are necessary to evaluate the clinical implications of this research.

Topics: Acetates; Animals; Anticonvulsants; Blotting, Western; Convulsants; Cyclopropanes; Kindling, Neurologic; Leukotriene Antagonists; Male; Mice; Pentylenetetrazole; Phenobarbital; Quinolines; Receptors, Leukotriene; Seizures; Sulfides; Time Factors; Treatment Outcome

Topics: Acetates; Adolescent; Asthma; Child; Child, Preschool; Cyclopropanes; Epilepsy; Female; Humans; Leukotriene Antagonists; Male; Quinolines; Receptors, Leukotriene; Rhinitis, Allergic; Seizures; Sulfides; Withholding Treatment

Although leukotrienes have been implicated in seizures, no study has systematically investigated whether the blockade of CysLT1 receptors synergistically increases the anticonvulsant action of classic antiepileptics. In this study, behavioral and electroencephalographic methods, as well as isobolographic analysis, are used to show that the CysLT1 inverse agonist montelukast synergistically increases the anticonvulsant action of phenobarbital against pentylenetetrazole-induced seizures. Moreover, it is shown that LTD4 reverses the effect of montelukast. The experimentally derived ED50mix value for a fixed-ratio combination (1:1 proportion) of montelukast plus phenobarbital was 0.06±0.02 μmol, whereas the additively calculated ED50add value was 0.49±0.03 μmol. The calculated interaction index was 0.12, indicating a synergistic interaction. The association of montelukast significantly decreased the antiseizure ED50 for phenobarbital (0.74 and 0.04 μmol in the absence and presence of montelukast, respectively) and, consequently, phenobarbital-induced sedation at equieffective doses. The demonstration of a strong synergism between montelukast and phenobarbital is particularly relevant because both drugs are already used in the clinics, foreseeing an immediate translational application for epileptic patients who have drug-resistant seizures.

Topics: Acetates; Animals; Anticonvulsants; Convulsants; Cyclopropanes; Dose-Response Relationship, Drug; Drug Synergism; Electroencephalography; Female; Leukotriene Antagonists; Mice; Motor Activity; Pentylenetetrazole; Phenobarbital; Quinolines; Seizures; Sulfides

Montelukast is an antiinflammatory drug with an antioxidant property. In this study, we aimed to reveal whether montelukast has a preventive effect against seizures and post-seizure oxidative stress in pentylenetetrazol (PTZ)-induced seizures in rats.. Of the 48 male Sprague-Dawley rats used in the study, 24 were assigned to EEG recordings (group A) and 24 were assigned to behavioral studies (group B). In group A, the electrodes were implanted on dura over the left frontal cortex for EEG recording. After 10 days, in group A, i.p. saline, 25, 50, or 100 mg/kg montelukast+35 mg/kg PTZ was administered to the rats. EEG was recorded and spike percentage was evaluated. In group B, i.p. saline, 25, 50, or 100 mg/kg montelukast+70 mg/kg PTZ was administered to the rats. Racine's Convulsion Scale (RCS) and onset times of first myoclonic jerk (FMJ) was used to evaluate the seizures. Malondialdehyde (MDA) and superoxide dismutase (SOD) levels were determined in the brain tissue of animals.. Animals treated with 50 or 100 mg/kg montelukast had significantly lower RCS and significantly increased FMJ onset time compared to the saline-treated animals. Moreover, groups given 25, 50, or 100 mg/kg montelukast had significantly lower MDA and higher SOD levels compared to the saline-treated group. The differences were more pronounced in the 100 mg/kg montelukast-pretreated group (p<0.001).. Montelukast showed anticonvulsant action and led to amelioration of oxidative stress markers in PTZ-induced seizures in rats.

Topics: Acetates; Action Potentials; Animals; Brain; Cyclopropanes; Electroencephalography; Male; Malondialdehyde; Pentylenetetrazole; Quinolines; Rats, Sprague-Dawley; Seizures; Sulfides; Superoxide Dismutase; Time Factors

Current evidence suggests that inflammation plays a role in the pathophysiology of seizures. In line with this view, selected pro-inflammatory arachidonic acid derivatives have been reported to facilitate seizures. Kainate-induced seizures are accompanied by leukotriene formation, and are reduced by inhibitors of LOX/COX pathway. Moreover, LTD4 receptor blockade and LTD4 synthesis inhibition suppress pentylenetetrazol (PTZ)-induced kindling and pilocarpine-induced recurrent seizures. Although there is convincing evidence supporting that blood-brain-barrier (BBB) dysfunction facilitates seizures, no study has investigated whether the anticonvulsant effect of montelukast is associated with its ability to maintain BBB integrity. In this study we investigated whether montelukast and other CysLT receptor antagonists decrease PTZ-induced seizures, as well as whether these antagonists preserve BBB during PTZ-induced seizures. Adult male albino Swiss mice were stereotaxically implanted with a cannula into the right lateral ventricle, and two electrodes were placed over the parietal cortex along with a ground lead positioned over the nasal sinus for electroencephalography (EEG) recording. The effects of montelukast (0.03 or 0.3 μmol/1 μL, i.c.v.), pranlukast (1 or 3 μmol/1 μL, i.c.v.), Bay u-9773 (0.3, 3 or 30 nmol/1 μL, i.c.v.), in the presence or absence of the agonist LTD4 (0.2, 2, 6 or 20 pmol/1 μL, i.c.v.), on PTZ (1.8 μmol/2 μL)-induced seizures and BBB permeability disruption were determined. The animals were injected with the antagonists, agonist or vehicle 30 min before PTZ, and monitored for additional 30 min for the appearance of seizures by electrographic and behavioral methods. BBB permeability was assessed by sodium fluorescein method and by confocal microscopy for CD45 and IgG immunoreactivity. Bay-u9973 (3 and 30 nmol), montelukast (0.03 and 0.3 μmol) and pranlukast (1 and 3 μmol), increased the latency to generalized seizures and decreased the mean amplitude of EEG recordings during seizures. LTD4 (0.2 and 2 pmol) reverted the anticonvulsant effect of montelukast (0.3 μmol). Montelukast (0.03 and 0.3 μmol) prevented PTZ-induced BBB disruption, an effect that was reversed by LTD4 at the dose of 6 pmol, but not at the doses 0.2 and 2 pmol. Moreover, the doses of LTD4 (0.2 and 2 pmol) that reverted the effect of montelukast on seizures did not alter montelukast-induced protection of BBB, dissociating BBB protection and anticonvulsant activity. Confoc

Topics: Acetates; Animals; Anticonvulsants; Blood-Brain Barrier; Brain; Capillary Permeability; Chromones; Cyclopropanes; Dose-Response Relationship, Drug; Immunoglobulin G; Leukocyte Common Antigens; Leukocytes; Leukotriene Antagonists; Leukotriene D4; Male; Mice; Neuroprotective Agents; Pentylenetetrazole; Quinolines; Receptors, Leukotriene; Seizures; SRS-A; Sulfides

The present study has been designed to pharmacologically investigate the effect of Montelukast sodium, a leukotriene D(4) receptor antagonist, and 1,2,3,4, tetrahydroisoquinoline, a leukotriene D(4) synthetic pathway inhibitor, on the pathophysiological progression of seizures using mouse models of kindled epilepsy and status epilepticus induced spontaneous recurrent seizures. Pentylenetetrazole (40 mg kg(-1)) (PTZ) administration every second day for a period of 15 d was used to elicit chemically induced kindled seizure activity in mice. In a separate set of groups, fifty consecutive electroshocks were delivered to mice using corneal electrodes with continuously increasing intensity with an inter-shock interval of 40s. Severity of kindled seizures was assessed in terms of a composite kindled seizure severity score (KSSS). Pilocarpine (100 mg kg(-1)) was injected every twenty minutes until the onset of status epilepticus. A spontaneous recurrent seizure severity score (SRSSS) was recorded as a measure of quantitative assessment of the progressive development of spontaneous recurrent seizures induced after pilocarpine status epilepticus. Sub-acute PTZ administration and electroshock induced the development of severe form of kindled seizures in mice. Severity of kindled seizures was assessed in terms of a composite kindled seizure severity score. Further, pharmacological status epilepticus elicited a progressive evolution of spontaneous recurrent seizures in the animals. However, Montelukast sodium, a leukotriene D(4) receptor antagonist, as well as 1,2,3,4, tetrahydroisoquinoline, a leukotriene D(4) synthetic pathway inhibitor, markedly and dose dependently suppressed the development of kindled seizures as well as pilocarpine induced spontaneous recurrent seizures. Therefore, leukotriene D(4) may be implicated in the pathogenesis of seizures.

Topics: Acetates; Animals; Cyclopropanes; Dose-Response Relationship, Drug; gamma-Glutamyltransferase; Leukotriene Antagonists; Leukotriene D4; Male; Mice; Models, Animal; Pilocarpine; Quinolines; Receptors, Leukotriene; Seizures; Sulfides; Tetrahydroisoquinolines

Topics: Acetates; Adrenal Cortex Hormones; Aged; Albuterol; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Arthritis; Asthma; Cyclopropanes; Depression; Drug Hypersensitivity; Drug Therapy, Combination; Epinephrine; Female; Humans; Hypersensitivity; Hypertension; Methylprednisolone; Omalizumab; Quinolines; Rhinitis; Salmeterol Xinafoate; Seizures; Sulfides; Syncope