CIBICI   14215
CENTRO DE INVESTIGACION EN BIOQUIMICA CLINICA E INMUNOLOGIA
Unidad Ejecutora - UE
artículos
Título:
Cysteinyl leukotriene receptor (CysLT) antagonists decrease pentylenetetrazol-induced seizures and blood-brain barrier dysfunction
Autor/es:
LENZ, QF; ARROYO, DS; TEMP, FR; POERSCH, AB; MASSON, CJ; JESSE, AC; MARAFIGA, JR; RESCHKE, CR; IRIBARREN, P; MELLO, CF
Revista:
NEUROSCIENCE
Editorial:
PERGAMON-ELSEVIER SCIENCE LTD
Referencias:
Lugar: Amsterdam; Año: 2014
ISSN:
0306-4522
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.