Montelucaste diminui as crises convulsivas em animais abrasados e potencializa o efeito anticonvulsivante do fenobarbital
Autor(a) principal: | |
---|---|
Data de Publicação: | 2015 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Repositório Institucional Manancial UFSM |
Texto Completo: | http://repositorio.ufsm.br/handle/1/3855 |
Resumo: | Epilepsy is a chronic neurological disease characterized by recurrent, unprovoked seizures. Evidence suggests that inflammation plays a role in the pathophysiology of seizures. Although cysteinyl leukotrienes (CysLTs) have been implicated in seizures, no study has investigated whether blocking of CysLT1 receptors potentiates the anticonvulsant action of classic antiepileptic drugs, as well as the expression of CysLT receptors is altered by inflammation. In this study we showed that the inverse agonist of CysLT1 receptor, montelukast, synergistically increases the anticonvulsant action of phenobarbital against seizures induced in a model of acute injection of pentylenetetrazole (PTZ). Furthermore, it is shown that LTD4 (leukotriene D4) prevents the effect of montelukast. Isobolographic analysis revealed an ED50 mix value for a fixed-ratio combination (1:1 proportion) of montelukast plus phenobarbital of 0.06 ± 0.02 μmol, whereas the calculated ED50 add value was 0.49 ± 0.03 μmol. The interaction index was 0.12, indicating a synergistic interaction. Montelukast significantly decreased the antiseizure DE50 for phenobarbital (0.74 and 0.04 μmol in the absence and presence of montelukast, respectively) and, consequently, phenobarbital-induced sedation at equieffective doses. We also investigated whether the CysLT1 inverse agonist montelukast and a classical anticonvulsant, phenobarbital, decrease seizures in PTZ-kindled mice and CysLT receptor expression. Montelukast (10 mg/kg, s.c.) and phenobarbital (20 mg/kg, s.c.) 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 seem to emerge as promising adjunct therapeutic agents in the treatment of refractory seizures. Notwithstanding, additional studies are necessary to evaluate the clinical implications of this work. |
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2016-04-052016-04-052015-07-28FLECK, Juliana. MONTELUKAST DECREASES SEIZURES IN KINDLED ANIMALS AND POTENTIATES THE ANTICONVULSANT EFFECT OF PHENOBARBITAL. 2015. 100 f. Tese (Doutorado em Farmácia) - Universidade Federal de Santa Maria, Santa Maria, 2015.http://repositorio.ufsm.br/handle/1/3855Epilepsy is a chronic neurological disease characterized by recurrent, unprovoked seizures. Evidence suggests that inflammation plays a role in the pathophysiology of seizures. Although cysteinyl leukotrienes (CysLTs) have been implicated in seizures, no study has investigated whether blocking of CysLT1 receptors potentiates the anticonvulsant action of classic antiepileptic drugs, as well as the expression of CysLT receptors is altered by inflammation. In this study we showed that the inverse agonist of CysLT1 receptor, montelukast, synergistically increases the anticonvulsant action of phenobarbital against seizures induced in a model of acute injection of pentylenetetrazole (PTZ). Furthermore, it is shown that LTD4 (leukotriene D4) prevents the effect of montelukast. Isobolographic analysis revealed an ED50 mix value for a fixed-ratio combination (1:1 proportion) of montelukast plus phenobarbital of 0.06 ± 0.02 μmol, whereas the calculated ED50 add value was 0.49 ± 0.03 μmol. The interaction index was 0.12, indicating a synergistic interaction. Montelukast significantly decreased the antiseizure DE50 for phenobarbital (0.74 and 0.04 μmol in the absence and presence of montelukast, respectively) and, consequently, phenobarbital-induced sedation at equieffective doses. We also investigated whether the CysLT1 inverse agonist montelukast and a classical anticonvulsant, phenobarbital, decrease seizures in PTZ-kindled mice and CysLT receptor expression. Montelukast (10 mg/kg, s.c.) and phenobarbital (20 mg/kg, s.c.) 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 seem to emerge as promising adjunct therapeutic agents in the treatment of refractory seizures. Notwithstanding, additional studies are necessary to evaluate the clinical implications of this work.A epilepsia é uma doença que se manifesta por crises epilépticas recorrentes, não provocadas. Evidências sugerem que a inflamação desempenha um papel na patofisiologia destas crises. Embora os leucotrienos cisteínicos (CysLTs) tenham sido implicados no desenvolvimento de crises convulsivas, nenhum estudo investigou se o bloqueio dos receptores CysLT1 potencializa a ação anticonvulsivante de antiepilépticos clássicos, assim como se a expressão dos receptores de CysLT é alterada por inflamação. Neste estudo mostramos que o agonista inverso de CysLT1, montelucaste, sinergicamente aumenta a ação anticonvulsivante do fenobarbital contra crises convulsivas induzidas em um modelo de injeção aguda de pentilenotetrazol (PTZ). Além disso, é mostrado que o LTD4 (leucotrieno D4) previne o efeito do montelucaste. A análise isobolográfica revelou que o valor de DE50 mix, calculado experimentalmente para uma combinação de proporção 1: 1 de montelucaste e fenobarbital foi de 0,06 ± 0,02 umol, ao passo que o valor de DE50 add, calculado foi de 0,49 ± 0,03 umol. O índice de interação encontrado foi de 0,12, indicando uma interação sinérgica. A associação dos fármacos diminuiu significativamente o DE50 para o efeito anticonvulsivante do fenobarbital de 0,74 para 0,04 umol (na ausência e na presença de montelucaste, respectivamente) e, consequentemente, a sedação induzida por fenobarbital em doses equieficazes. Posteriormente foi avaliado se o montelucaste e o fenobarbital diminuem as crises convulsivas em animais previamente abrasados, assim como se o tratamento farmacológico ou o abrasamento alteram a expressão de receptores CysLTs. O montelucaste (10 mg/kg; s.c.) e o fenobarbital (20 mg/kg, s.c.) aumentaram a latência para crises convulsivas generalizadas em camundongos abrasados. O montelucaste aumentou a imunorreatividade do receptor CysLT1 em camundongos não abrasados e que foram desafiados por PTZ que não foram abrasados. Entretanto, o desafio de PTZ diminuiu a imunorreatividade do receptor CysLT2 apenas em camundongos abrasados. Antagonistas do receptor CysLT1 parecem emergir como agentes terapêuticos adjuntos promissores no tratamento de crises refratárias. Não obstante, estudos adicionais são necessários para avaliar as implicações clínicas deste trabalho.application/pdfporUniversidade Federal de Santa MariaPrograma de Pós-Graduação em FarmacologiaUFSMBRFarmacologiaEpilepsiaNeuroinflamaçãoPentilenotetrazolCysLT1CysLT2EpilepsyNeuroinflammationPentilenotetrazoleCysLT1CysLT2CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIAMontelucaste diminui as crises convulsivas em animais abrasados e potencializa o efeito anticonvulsivante do fenobarbitalMontelukast decreases seizures in kindled animals and potentiates the anticonvulsant effect of phenobarbitalinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisMello, Carlos Fernando dehttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4782674D2Jesse, Cristiano Ricardohttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4717707A3Leal, Daniela Bitencourt Rosahttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4706487E7Rosemberg, Denis Broockhttp://lattes.cnpq.br/7713953979203056Cunha, Mauro Alves dahttp://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4760089U8http://lattes.cnpq.br/1497762896019410Fleck, Juliana20100000000040050030030030030050082e537b0-4a43-400e-9f82-0cd91952adea3be6fe54-0a14-453f-a2f9-27263d4c3b4a288da5c4-855a-4f9e-a357-c33d01032a48c557ce44-0763-4865-8372-1163d96ba82bbec1216c-bf03-46b6-acdc-42be8d1d864bf9191853-83b2-4201-b787-710a9d4fd58dinfo:eu-repo/semantics/openAccessreponame:Repositório Institucional Manancial UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALFLECK, JULIANA.pdfapplication/pdf2044828http://repositorio.ufsm.br/bitstream/1/3855/1/FLECK%2c%20JULIANA.pdfab8b86f2b1555b1bed5db39c5317f4fbMD51TEXTFLECK, JULIANA.pdf.txtFLECK, JULIANA.pdf.txtExtracted texttext/plain174031http://repositorio.ufsm.br/bitstream/1/3855/2/FLECK%2c%20JULIANA.pdf.txt6cce79a584b2bb4127ac614247924d38MD52THUMBNAILFLECK, JULIANA.pdf.jpgFLECK, JULIANA.pdf.jpgIM Thumbnailimage/jpeg5142http://repositorio.ufsm.br/bitstream/1/3855/3/FLECK%2c%20JULIANA.pdf.jpg18a8cd889d2c2c0cd7b3157d1694205cMD531/38552022-01-06 14:45:51.545oai:repositorio.ufsm.br:1/3855Repositório Institucionalhttp://repositorio.ufsm.br/PUBhttp://repositorio.ufsm.br/oai/requestouvidoria@ufsm.bropendoar:39132022-01-06T17:45:51Repositório Institucional Manancial UFSM - Universidade Federal de Santa Maria (UFSM)false |
dc.title.por.fl_str_mv |
Montelucaste diminui as crises convulsivas em animais abrasados e potencializa o efeito anticonvulsivante do fenobarbital |
dc.title.alternative.eng.fl_str_mv |
Montelukast decreases seizures in kindled animals and potentiates the anticonvulsant effect of phenobarbital |
title |
Montelucaste diminui as crises convulsivas em animais abrasados e potencializa o efeito anticonvulsivante do fenobarbital |
spellingShingle |
Montelucaste diminui as crises convulsivas em animais abrasados e potencializa o efeito anticonvulsivante do fenobarbital Fleck, Juliana Epilepsia Neuroinflamação Pentilenotetrazol CysLT1 CysLT2 Epilepsy Neuroinflammation Pentilenotetrazole CysLT1 CysLT2 CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Montelucaste diminui as crises convulsivas em animais abrasados e potencializa o efeito anticonvulsivante do fenobarbital |
title_full |
Montelucaste diminui as crises convulsivas em animais abrasados e potencializa o efeito anticonvulsivante do fenobarbital |
title_fullStr |
Montelucaste diminui as crises convulsivas em animais abrasados e potencializa o efeito anticonvulsivante do fenobarbital |
title_full_unstemmed |
Montelucaste diminui as crises convulsivas em animais abrasados e potencializa o efeito anticonvulsivante do fenobarbital |
title_sort |
Montelucaste diminui as crises convulsivas em animais abrasados e potencializa o efeito anticonvulsivante do fenobarbital |
author |
Fleck, Juliana |
author_facet |
Fleck, Juliana |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Mello, Carlos Fernando de |
dc.contributor.advisor1Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4782674D2 |
dc.contributor.referee1.fl_str_mv |
Jesse, Cristiano Ricardo |
dc.contributor.referee1Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4717707A3 |
dc.contributor.referee2.fl_str_mv |
Leal, Daniela Bitencourt Rosa |
dc.contributor.referee2Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4706487E7 |
dc.contributor.referee3.fl_str_mv |
Rosemberg, Denis Broock |
dc.contributor.referee3Lattes.fl_str_mv |
http://lattes.cnpq.br/7713953979203056 |
dc.contributor.referee4.fl_str_mv |
Cunha, Mauro Alves da |
dc.contributor.referee4Lattes.fl_str_mv |
http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4760089U8 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/1497762896019410 |
dc.contributor.author.fl_str_mv |
Fleck, Juliana |
contributor_str_mv |
Mello, Carlos Fernando de Jesse, Cristiano Ricardo Leal, Daniela Bitencourt Rosa Rosemberg, Denis Broock Cunha, Mauro Alves da |
dc.subject.por.fl_str_mv |
Epilepsia Neuroinflamação Pentilenotetrazol CysLT1 CysLT2 |
topic |
Epilepsia Neuroinflamação Pentilenotetrazol CysLT1 CysLT2 Epilepsy Neuroinflammation Pentilenotetrazole CysLT1 CysLT2 CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
dc.subject.eng.fl_str_mv |
Epilepsy Neuroinflammation Pentilenotetrazole CysLT1 CysLT2 |
dc.subject.cnpq.fl_str_mv |
CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
Epilepsy is a chronic neurological disease characterized by recurrent, unprovoked seizures. Evidence suggests that inflammation plays a role in the pathophysiology of seizures. Although cysteinyl leukotrienes (CysLTs) have been implicated in seizures, no study has investigated whether blocking of CysLT1 receptors potentiates the anticonvulsant action of classic antiepileptic drugs, as well as the expression of CysLT receptors is altered by inflammation. In this study we showed that the inverse agonist of CysLT1 receptor, montelukast, synergistically increases the anticonvulsant action of phenobarbital against seizures induced in a model of acute injection of pentylenetetrazole (PTZ). Furthermore, it is shown that LTD4 (leukotriene D4) prevents the effect of montelukast. Isobolographic analysis revealed an ED50 mix value for a fixed-ratio combination (1:1 proportion) of montelukast plus phenobarbital of 0.06 ± 0.02 μmol, whereas the calculated ED50 add value was 0.49 ± 0.03 μmol. The interaction index was 0.12, indicating a synergistic interaction. Montelukast significantly decreased the antiseizure DE50 for phenobarbital (0.74 and 0.04 μmol in the absence and presence of montelukast, respectively) and, consequently, phenobarbital-induced sedation at equieffective doses. We also investigated whether the CysLT1 inverse agonist montelukast and a classical anticonvulsant, phenobarbital, decrease seizures in PTZ-kindled mice and CysLT receptor expression. Montelukast (10 mg/kg, s.c.) and phenobarbital (20 mg/kg, s.c.) 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 seem to emerge as promising adjunct therapeutic agents in the treatment of refractory seizures. Notwithstanding, additional studies are necessary to evaluate the clinical implications of this work. |
publishDate |
2015 |
dc.date.issued.fl_str_mv |
2015-07-28 |
dc.date.accessioned.fl_str_mv |
2016-04-05 |
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2016-04-05 |
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info:eu-repo/semantics/publishedVersion |
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info:eu-repo/semantics/doctoralThesis |
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doctoralThesis |
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publishedVersion |
dc.identifier.citation.fl_str_mv |
FLECK, Juliana. MONTELUKAST DECREASES SEIZURES IN KINDLED ANIMALS AND POTENTIATES THE ANTICONVULSANT EFFECT OF PHENOBARBITAL. 2015. 100 f. Tese (Doutorado em Farmácia) - Universidade Federal de Santa Maria, Santa Maria, 2015. |
dc.identifier.uri.fl_str_mv |
http://repositorio.ufsm.br/handle/1/3855 |
identifier_str_mv |
FLECK, Juliana. MONTELUKAST DECREASES SEIZURES IN KINDLED ANIMALS AND POTENTIATES THE ANTICONVULSANT EFFECT OF PHENOBARBITAL. 2015. 100 f. Tese (Doutorado em Farmácia) - Universidade Federal de Santa Maria, Santa Maria, 2015. |
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http://repositorio.ufsm.br/handle/1/3855 |
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Universidade Federal de Santa Maria |
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UFSM |
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BR |
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Farmacologia |
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Universidade Federal de Santa Maria |
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