leukotriene-d4 and Seizures

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

Using low frequency (quenching) stimulation parameters (1 Hz for 15 min), similar to those that induce long-term depression (LTD) in vitro, we attempted to alter amygdala kindling in vivo in rats. Quenching completely blocked the development and progression of after-discharges and seizures in seven of eight animals. In fully kindled animals, once-daily quenching stimulation for one week (without concurrent kindling) suppressed the seizures when kindling stimulation was resumed. These effects of quenching probably resulted from the marked and long-lasting increases in the afterdischarge and seizure thresholds that were observed in these animals. These data indicate that quenching with low frequency electrical stimulation (which does not disrupt ongoing behavior) can have profound and long-lasting effects on seizure development, expression, and thresholds. The ultimate clinical applicability of low frequency stimulation in the treatment of seizures and related neuropsychiatric disorders remains to be explored.

Topics: Amygdala; Animals; Electric Stimulation Therapy; Kindling, Neurologic; Leukotriene D4; Male; Rats; Rats, Sprague-Dawley; Seizures