RESUMO
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.
Assuntos
Anticonvulsivantes/farmacologia , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Antagonistas de Leucotrienos/farmacologia , Fármacos Neuroprotetores/farmacologia , Convulsões/tratamento farmacológico , Acetatos/farmacologia , Animais , Barreira Hematoencefálica/fisiopatologia , Encéfalo/fisiopatologia , Permeabilidade Capilar/efeitos dos fármacos , Permeabilidade Capilar/fisiologia , Cromonas/farmacologia , Ciclopropanos , Relação Dose-Resposta a Droga , Imunoglobulina G/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/fisiologia , Leucotrieno D4/farmacologia , Masculino , Camundongos , Pentilenotetrazol , Quinolinas/farmacologia , Receptores de Leucotrienos/agonistas , Receptores de Leucotrienos/metabolismo , SRS-A/análogos & derivados , SRS-A/farmacologia , Convulsões/fisiopatologia , SulfetosRESUMO
The effect of econazole on the release of thromboxanes was investigated. It was found that econazole inhibited concentration-dependently the aggregation of guinea pig platelets stimulated with arachidonic acid. The compound also reduced significantly the LTB4-induced contraction of guinea pig lung parenchyma strips and the contraction of rabbit aorta to the effluent of LTD4-stimulated guinea pig lungs, both effects mediated mostly by thromboxane generation. The concentration of TXB2 in the effluents from LTD4 stimulated lungs, assayed by EIA, was significantly reduced following pretreatment of the lungs with 10(-4) M and 10(-5) M of econazole, whereas the levels of PGE2 were increased. These results demonstrate that econazole is a selective inhibitor of thromboxane synthesis.
Assuntos
Econazol/farmacologia , Tromboxanos/fisiologia , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Ácido Araquidônico/farmacologia , Dinoprostona/metabolismo , Cobaias , Leucotrieno B4/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/fisiologia , Masculino , Contração Muscular/efeitos dos fármacos , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Coelhos , SRS-A/farmacologia , Tromboxano B2/metabolismoRESUMO
The purpose of these studies was to evaluate the effects of the peptidoleukotriene (LT) receptor antagonist, ICI 198615, on the vasopressor responses produced by LTC4, LTD4 and LTE4. Conscious, normotensive rats were prepared with arterial and venous catheters for measurement of changes in arterial blood pressure and administration of drugs, respectively. Complete dose-response curves were first generated to LTC4, LTD4 and LTE4: those agents produced dose-dependent increases in arterial blood pressure, with ED20 values (i.e. dose to increase blood pressure 20 mm Hg) of 1.7 +/- 0.2, 2.1 +/- 0.2 and 19.8 +/- 3.7 nmol/kg i.v., respectively. ICI 198615 (intravenous bolus followed by a continuous infusion) produced dose-dependent, parallel shifts to the right in the LTC4 dose-response curve. At doses of 0.2 mg/kg + 1 mg/kg/h, 1 mg/kg + 3 mg/kg/h or 2 mg/kg + 10 mg/kg/h, ICI 198615 produced dose ratios of 4.5, 17.1 and 50.0, respectively. Against LTD4 responses, ICI 198615 at a dose of 0.1 mg/kg + 0.3 mg/kg/h produced a dose ratio of 3.4, whereas at doses of 0.2 mg/kg + 1 mg/kg/h, 1 mg/kg + 3 mg/kg/h or 2 mg/kg + 10 mg/kg/h ICI 198615 produced dose ratios of 16.3, 24.9 and 16.2, respectively. The difference in the dose ratios between these three groups was not statistically significant (p greater than 0.05). However, a dose of 10 mg/kg + 30 mg/kg/h produced a dose ratio of greater than 100. Against LTE4 responses, ICI 198615 at doses of 0.2 mg/kg + 1 mg/kg/h or 1 mg/kg + 3 mg/kg/h produced dose ratios of 4.1 and 11.3, respectively. The similarity in the LTD4 dose ratios despite a 3- or 10-fold increase in the dose of ICI 198615 suggests the existence of high- and low-affinity LTD4 receptor sites, whereas the responses to LTC4 and LTE4 appeared to be mediated via a single receptor population. These results indicate that ICI 198615 is a potent and competitive antagonist of LTC4, LTD4 and LTE4 vascular responses in the rat.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Indazóis/farmacologia , SRS-A/análogos & derivados , SRS-A/antagonistas & inibidores , Animais , Relação Dose-Resposta a Droga , Indazóis/administração & dosagem , Infusões Intravenosas , Leucotrieno E4 , Masculino , Ratos , Ratos Endogâmicos , Receptores Imunológicos/antagonistas & inibidores , Receptores de Leucotrienos , SRS-A/farmacologia , Vasoconstrição/efeitos dos fármacosRESUMO
The effects of leukotriene C4 (LTC4), nordihydroguaiaretic acid (NDGA) and FPL-55712, on the metabolism of labelled glucose (U14C-glucose) in uteri isolated from spayed rats and from spayed-estrogenized rats, incubated in the presence and in the absence of indomethacin, were explored. Indomethacin (10(-6)M), enhanced significantly 14CO2 formation from labelled glucose, both in uteri from ovariectomized rats and in uteri from ovariectomized-estrogenized animals. In uteri from spayed not-estrogenized rats, expose 'in vitro' to indomethacin, NDGA (10(-5)M), an inhibitor of the 5-lipoxygenase, as well as FPL-55712 (10(-5)M), a LT antagonist, reduced significantly the enhanced metabolism of glucose evoked by indomethacin, an inhibitor of the cyclo- oxygenase. On the other hand, LTC4 (10(-7)M), augmented the metabolism of labelled glucose, reaching values even greater than those induced by indomethacin. In the spayed-estrogenized group LTC4 (10(-10)-10(-7)M) enhanced the formation of labelled CO2 from labelled glucose as much as indomethacin (10(-6)M) did, whereas neither NDGA nor FPL-55712 were effective. In addition, in uteri from ovariectomized-estrogenized rats, incubated with indomethacin, NDGA and FPL-55712, decreased the augmenting action of indomethacin on glucose metabolism, whereas LTC4 (10(-10)-10(-7)M) evoked a complete reversal of the inhibitory influence of NDGA on the formation of 14CO2. The force-going results suggest that tissue 5-lipoxygenase products, particularly LTC4, are involved in the metabolism of labelled glucose by rat uteri, mainly when the cyclo-oxygenase pathway is inhibited by indomethacin and the tissue is deprived of estradiol.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Estradiol/farmacologia , Glucose/metabolismo , Indometacina/farmacologia , SRS-A/farmacologia , Útero/metabolismo , Animais , Dióxido de Carbono/metabolismo , Cromonas/farmacologia , Feminino , Técnicas In Vitro , Masoprocol/farmacologia , Ovariectomia , Ratos , Ratos Endogâmicos , Útero/enzimologiaRESUMO
Wy-45,911 (4-[hydroxy-[3-(2-quinolinylmethoxy)phenyl] amino]-4-oxabutanoic acid, methyl ester) was found to inhibit competitively leukotriene D4 (LTD4)-induced contractions of the isolated guinea pig trachea but not those of leukotriene C4 (LTC4), even in the presence of a gamma-glutamyltranspeptidase inhibitor, reduced glutathione (GSH). Tracheal contractions induced by histamine or pilocarpine were also not significantly altered by Wy-45,911. The drug inhibited the tracheal contractions induced by antigen, even in the presence of GSH. This latter effect resulted from inhibition of 5-lipoxygenase (5-LO), as the synthesis of 5-LO products by rat polymorphonuclear leukocytes and by mouse macrophages was markedly reduced by Wy-45,911. The drug inhibited both LTD4-induced and antigen-induced bronchoconstriction when injected intraduodenally or intragastrically into intact guinea pigs though it was more potent against LTD4-induced bronchoconstriction. We conclude that Wy-45,911 is a novel, orally active LTD4 antagonist in the guinea pig, with some 5-LO inhibitory activity.
Assuntos
Antígenos/imunologia , Asma/imunologia , Quinolinas/farmacologia , Receptores de Prostaglandina/antagonistas & inibidores , SRS-A/farmacologia , Animais , Ácido Araquidônico , Ácidos Araquidônicos/metabolismo , Asma/induzido quimicamente , Inibidores de Ciclo-Oxigenase , Cobaias , Inibidores de Lipoxigenase , Macrófagos/metabolismo , Masculino , Contração Muscular/efeitos dos fármacos , Cavidade Peritoneal/citologia , Receptores de Leucotrienos , Tromboxano B2/biossíntese , Traqueia/efeitos dos fármacos , Traqueia/fisiologiaRESUMO
The effect of lipoxygenase inhibition, leukotriene agonists and antagonists, and 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) was examined in the rat pineal gland in organ culture. To study melatonin secretion pineal explants were incubated for 6 h in tissue culture medium 199 with the different drugs. Melatonin concentration in the pineal gland and the medium was measured by RIA. Exposure of explants to norepinephrine (NE) brought about a 2- to 5-fold increase in both parameters, an effect that was reduced but not abolished, by the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA; 10(-5) M). Lilly 171883 (10(-5) M) or FPL 55712 (10(-5) M; both antagonists of leukotrienes) reduced NE-induced melatonin production. Neither NDGA nor Lilly 171883 affected melatonin production in the absence of NE. Leukotrienes C4 and D4 increased melatonin release to the media at all concentrations tested (1-1,000 nM) with a maximum effect at 1 nM (leukotriene C4) and 10 nM (leukotriene D4). Significantly higher tissue melatonin concentrations as compared to controls were observed after exposure of pineal explants to 1 and 100 nM of leukotriene C4, or 100 nM of leukotriene D4. Another 5-lipoxygenase metabolite, 5-HETE, increased pineal melatonin content at concentrations of 1, 10 and 100 nM whereas only 1,000 nM stimulated melatonin release. These results suggest that the 5-lipoxygenase pathway plays a significant role in NE-stimulated melatonin production by the rat pineal gland.