| InChI | InChI=1S/C27H36O5S/c1-2-3-4-5-6-7-8-9-10-11-12-13-16-25(24(28)15-14-17-26(29)30)33-23-20-18-22(19-21-23)27(31)32/h6-7,9-13,16,18-21,24-25,28H,2-5,8,14-15,17H2,1H3,(H,29,30)(H,31,32)/b7-6-,10-9-,12-11+,16-13+/t24-,25+/m0/s1 |
| Reference | 1. Neuroscience. 2014 Sep 26;277:859-71. doi: 10.1016/j.neuroscience.2014.07.058.
Epub 2014 Aug 1.
<br>
Cysteinyl leukotriene receptor (CysLT) antagonists decrease
pentylenetetrazol-induced seizures and blood-brain barrier dysfunction.
<br>
Lenz QF(1), Arroyo DS(2), Temp FR(1), Poersch AB(3), Masson CJ(3), Jesse AC(3),
Marafiga JR(3), Reschke CR(1), Iribarren P(2), Mello CF(4).
<br>
Author information: <br>
(1)Departamento de Fisiologia e Farmacologia, Centro de Ciências da Saúde,
Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil; Programa de
Pós-Graduação em Farmacologia, Centro de Ciências da Saúde, Universidade Federal
de Santa Maria (UFSM), Santa Maria, RS, Brazil.
(2)Centro de Investigaciones en Bioquímica Clínica e Inmunología
(CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias
Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
(3)Departamento de Fisiologia e Farmacologia, Centro de Ciências da Saúde,
Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil.
(4)Departamento de Fisiologia e Farmacologia, Centro de Ciências da Saúde,
Universidade Federal de Santa Maria (UFSM), Santa Maria, RS, Brazil; Programa de
Pós-Graduação em Farmacologia, Centro de Ciências da Saúde, Universidade Federal
de Santa Maria (UFSM), Santa Maria, RS, Brazil. Electronic address:
[email protected].
<br>
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.
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