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1.
Braz J Med Biol Res ; 49(4): e5031, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26909785

RESUMEN

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.


Asunto(s)
Acetatos/farmacología , Anticonvulsivantes/farmacología , Antagonistas de Leucotrieno/farmacología , Quinolinas/farmacología , Convulsiones/tratamiento farmacológico , Acetatos/uso terapéutico , Animales , Anticonvulsivantes/uso terapéutico , Western Blotting , Convulsivantes , Ciclopropanos , Excitación Neurológica/efectos de los fármacos , Antagonistas de Leucotrieno/uso terapéutico , Masculino , Ratones , Pentilenotetrazol , Fenobarbital/farmacología , Fenobarbital/uso terapéutico , Quinolinas/uso terapéutico , Receptores de Leucotrienos/efectos de los fármacos , Convulsiones/inducido químicamente , Sulfuros , Factores de Tiempo , Resultado del Tratamiento
2.
Braz. j. med. biol. res ; 49(4): e5031, 2016. tab, graf
Artículo en Inglés | LILACS | ID: lil-774523

RESUMEN

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.


Asunto(s)
Animales , Masculino , Ratones , Acetatos/farmacología , Anticonvulsivantes/farmacología , Antagonistas de Leucotrieno/farmacología , Quinolinas/farmacología , Convulsiones/tratamiento farmacológico , Acetatos/uso terapéutico , Anticonvulsivantes/uso terapéutico , Western Blotting , Convulsivantes , Excitación Neurológica/efectos de los fármacos , Antagonistas de Leucotrieno/uso terapéutico , Pentilenotetrazol , Fenobarbital/farmacología , Fenobarbital/uso terapéutico , Quinolinas/uso terapéutico , Receptores de Leucotrienos/efectos de los fármacos , Convulsiones/inducido químicamente , Factores de Tiempo , Resultado del Tratamiento
3.
Neuroscience ; 277: 859-71, 2014 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-25090924

RESUMEN

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. Confocal microscopy analysis revealed that 1. PTZ increased the number of CD45+ and double-immunofluorescence staining for CD45 and IgG cells in the cerebral cortex, indicating BBB leakage with leukocyte infiltration; 2. while LTD4 (6 pmol) potentiated, montelukast decreased the effect of PTZ on leukocyte migration and BBB, assessed by double-immunofluorescence staining for CD45 and IgG cells in the cannulated hemisphere. Our data do not allow us ruling out that mechanisms unrelated and related to BBB protection may co-exist, resulting in decreased seizure susceptibility by montelukast. Notwithstanding, they suggest that CysLT1 receptors may be a suitable target for anticonvulsant development.


Asunto(s)
Anticonvulsivantes/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Encéfalo/efectos de los fármacos , Antagonistas de Leucotrieno/farmacología , Fármacos Neuroprotectores/farmacología , Convulsiones/tratamiento farmacológico , Acetatos/farmacología , Animales , Barrera Hematoencefálica/fisiopatología , Encéfalo/fisiopatología , Permeabilidad Capilar/efectos de los fármacos , Permeabilidad Capilar/fisiología , Cromonas/farmacología , Ciclopropanos , Relación Dosis-Respuesta a Droga , Inmunoglobulina G/metabolismo , Antígenos Comunes de Leucocito/metabolismo , Leucocitos/efectos de los fármacos , Leucocitos/fisiología , Leucotrieno D4/farmacología , Masculino , Ratones , Pentilenotetrazol , Quinolinas/farmacología , Receptores de Leucotrienos/agonistas , Receptores de Leucotrienos/metabolismo , SRS-A/análogos & derivados , SRS-A/farmacología , Convulsiones/fisiopatología , Sulfuros
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