Estudos dos mecanismos envolvidos na ação antinociceptiva causada pelo disseleneto de difenila em camundongos

Detalhes bibliográficos
Autor(a) principal: Savegnago, Lucielli
Data de Publicação: 2007
Tipo de documento: Tese
Idioma: por
Título da fonte: Biblioteca Digital de Teses e Dissertações do UFSM
Texto Completo: http://repositorio.ufsm.br/handle/1/4390
Resumo: The interest in organoselenium biochemistry and pharmacology has increased in the last two decades due to a variety of organoselenium compounds that possess biological activity. Accordingly, diphenyl diselenide, a simple diaryl diselenide, is known as a safety drug when administered acutely to mice at doses that have antiinflammatory and antinociceptive activities. Therefore, the research of the mechanisms by which this compound exerts its effects is extremely important for the therapeutic application. Based on the considerations above, the aims of the present study were to evaluate the acute toxicity induced by diphenyl diselenide in mice using oral route of administration with the purpose of offering safety in the use of this compound and to verify the antinociceptive and antiinflammatory activities caused by diphenyl diselenide as well as its mechanisms of action. Diphenyl diselenide administered orally produced minor toxicological effects which were evidenced by the index of mortality (lethal-dose > 312 mg/kg). Although diphenyl diselenide did not provide evidence for renal or hepatic toxicity, the body weight gain in mice exposed to this compound was reduced, which might indicate systemic toxicity. The oral administration (p.o.) of diphenyl diselenide inhibited acetic acid-induced abdominal constriction as well as capsaicin-, glutamate- bradykinin (BK)- phorbol myristate acetate (PMA)- and formalin induced nociception and caused a significant increase in tail-immersion response latency time. In addition, diphenyl diselenide co-injected intraplantarly (i.pl.) in association with glutamate induced a significant reduction of the licking and in the paw oedema formation induced by glutamate. The local pretreatment of mice with L-arginine and dithiothreitol (DTT; i.pl.) restored local antinociception caused by diphenyl diselenide when analyzed against glutamateinduced nociception. Moreover, diphenyl diselenide, given orally, caused significant inhibition of the biting behavior induced by intrathecal (i.t.) injection of glutamate, Nmethyl-D-aspartate (NMDA), substance P (SP), interleukin 1b (IL-1b), tumor necrosis factor-a (TNF-a), BK and capsaicin, but completely failed to affect the nociception induced by α-amino-3-hydroxy-5-mehtyl-4-isoxazolepropionic acid (AMPA), kainate and (±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD). The antinociceptive effect caused by diphenyl diselenide in the formalin test was reversed by i.t. injection of several K+ channel blockers such as apamin and charybdotoxin (large- and small-conductance Ca2+- activated K+ channel inhibitors, respectively), tetraethylammonium (TEA, non-selective voltage-dependent K+ channel inhibitor), but not glibenclamide (ATP-sensitive K+ channel inhibitor). Injection of mice with inhibitor of nitric oxide (NO) synthase (Nω-nitro-L-arginine; L-NOARG), guanylyl cyclase inhibitors (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one - ODQ; and methylene blue) and calcium chloride (CaCl2) significantly blocked the antinociceptive effect caused by diphenyl diselenide when assessed on the formalin test. In contrast, i.t. injection of pertussis toxin, an inactivator of Gi/0 protein, did not antagonize the antinociceptive action caused by diphenyl diselenide in the formalin test. Diphenyl diselenide increased nociceptive threshold in mechanical allodynia induced by both partial sciatic nerve ligation (neuropathic pain) and ACF i.pl. injection (inflammatory chronic pain) as well as attenuated acute thermal hyperalgesia induced by i.t. injection of glutamate, NMDA, BK and prostaglandin E2 (PGE2). Together these results suggested the participation of nitric oxide/cyclic GMP/Ca2+ and K+ channel, pathways, inhibition PKA e PKC, as well as glutamatergic, peptidergic and vanilloid systems in the antinociceptive action caused by diphenyl diselenide in mice.
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spelling 2017-04-242017-04-242007-08-01SAVEGNAGO, Lucielli. Studies of mechanisms involved in the antinociceptive action caused by diphenyl diselenide in mice. 2007. 172 f. Tese (Doutorado em Bioquímica) - Universidade Federal de Santa Maria, Santa Maria, 2007.http://repositorio.ufsm.br/handle/1/4390The interest in organoselenium biochemistry and pharmacology has increased in the last two decades due to a variety of organoselenium compounds that possess biological activity. Accordingly, diphenyl diselenide, a simple diaryl diselenide, is known as a safety drug when administered acutely to mice at doses that have antiinflammatory and antinociceptive activities. Therefore, the research of the mechanisms by which this compound exerts its effects is extremely important for the therapeutic application. Based on the considerations above, the aims of the present study were to evaluate the acute toxicity induced by diphenyl diselenide in mice using oral route of administration with the purpose of offering safety in the use of this compound and to verify the antinociceptive and antiinflammatory activities caused by diphenyl diselenide as well as its mechanisms of action. Diphenyl diselenide administered orally produced minor toxicological effects which were evidenced by the index of mortality (lethal-dose > 312 mg/kg). Although diphenyl diselenide did not provide evidence for renal or hepatic toxicity, the body weight gain in mice exposed to this compound was reduced, which might indicate systemic toxicity. The oral administration (p.o.) of diphenyl diselenide inhibited acetic acid-induced abdominal constriction as well as capsaicin-, glutamate- bradykinin (BK)- phorbol myristate acetate (PMA)- and formalin induced nociception and caused a significant increase in tail-immersion response latency time. In addition, diphenyl diselenide co-injected intraplantarly (i.pl.) in association with glutamate induced a significant reduction of the licking and in the paw oedema formation induced by glutamate. The local pretreatment of mice with L-arginine and dithiothreitol (DTT; i.pl.) restored local antinociception caused by diphenyl diselenide when analyzed against glutamateinduced nociception. Moreover, diphenyl diselenide, given orally, caused significant inhibition of the biting behavior induced by intrathecal (i.t.) injection of glutamate, Nmethyl-D-aspartate (NMDA), substance P (SP), interleukin 1b (IL-1b), tumor necrosis factor-a (TNF-a), BK and capsaicin, but completely failed to affect the nociception induced by α-amino-3-hydroxy-5-mehtyl-4-isoxazolepropionic acid (AMPA), kainate and (±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD). The antinociceptive effect caused by diphenyl diselenide in the formalin test was reversed by i.t. injection of several K+ channel blockers such as apamin and charybdotoxin (large- and small-conductance Ca2+- activated K+ channel inhibitors, respectively), tetraethylammonium (TEA, non-selective voltage-dependent K+ channel inhibitor), but not glibenclamide (ATP-sensitive K+ channel inhibitor). Injection of mice with inhibitor of nitric oxide (NO) synthase (Nω-nitro-L-arginine; L-NOARG), guanylyl cyclase inhibitors (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one - ODQ; and methylene blue) and calcium chloride (CaCl2) significantly blocked the antinociceptive effect caused by diphenyl diselenide when assessed on the formalin test. In contrast, i.t. injection of pertussis toxin, an inactivator of Gi/0 protein, did not antagonize the antinociceptive action caused by diphenyl diselenide in the formalin test. Diphenyl diselenide increased nociceptive threshold in mechanical allodynia induced by both partial sciatic nerve ligation (neuropathic pain) and ACF i.pl. injection (inflammatory chronic pain) as well as attenuated acute thermal hyperalgesia induced by i.t. injection of glutamate, NMDA, BK and prostaglandin E2 (PGE2). Together these results suggested the participation of nitric oxide/cyclic GMP/Ca2+ and K+ channel, pathways, inhibition PKA e PKC, as well as glutamatergic, peptidergic and vanilloid systems in the antinociceptive action caused by diphenyl diselenide in mice.Nos últimos anos, os compostos orgânicos de selênio têm sido alvos de interesse em síntese orgânica em virtude da descoberta de suas aplicações sintéticas e de suas propriedades farmacológicas. O disseleneto de difenila é um composto orgânico de selênio que apresenta baixa toxicidade quando administrado pela via subcutânea em camundongos, nas doses em que exerce ação antinociceptiva e antiinflamatória. Assim, a pesquisa dos mecanismos pelos quais esse composto exerce seus efeitos é importante para a sua aplicação biológica. Desta forma, no presente trabalho investigou-se a toxicidade aguda induzida pelo disseleneto de difenila quando administrado pela via oral em camundongos e as propriedades antinociceptiva e antiinflamatória desse composto, bem como os possíveis mecanismos envolvidos em tal processo. A administração oral do disseleneto de difenila causou baixa toxicidade o que foi evidenciado pelo índice de mortalidade (dose letal > 312 mg/kg). Apesar do disseleneto de difenila não ter apresentado evidências de toxicidade renal e hepática, o ganho de peso corporal dos camundongos foi reduzido, o que pode indicar toxicidade sistêmica causada por esse composto. A administração oral do disseleneto de difenila reduziu o número de contorções abdominais induzidas pelo ácido acético, bem como, preveniu a nocicepção induzida pela injeção intraplantar (i.pl.) de glutamato, capsaicina, formalina, bradicinina (BK) e acetato de forbol miristato (PMA). A administração oral do disseleneto de difenila foi capaz de prevenir a nocicepção térmica, no modelo da imersão da cauda a 55°C. O disseleneto de difenila co-injetado intraplantar com o glutamato causou redução significante na reposta nociceptiva induzida pelo glutamato, sendo que esse efeito antinociceptivo local foi bloqueado pelo prétratamento local com a L-arginina e com o ditiotreitol (DTT). Além disso, a administração oral do disseleneto de difenila preveniu a nocicepção induzida pela injeção intratecal (i.t.) de glutamato, ácido N-metil-D-aspártico (NMDA), capsaicina, BK, substância P (SP), fator de necrose alfa (TNF-a) e interleucina 1b (IL-1b), mas não bloqueou significativamente a nocicepção causada pela injeção i.t. do ácido α-amino-3-hidroxi-5-metil-4-isoxazolopropionico (AMPA), cainato e ácido (±)-1-aminociclopentano-trans-1,3-dicarboxílico (trans-ACPD). A antinocicepção causada pela administração oral do disseleneto de difenila no teste da formalina foi revertida pelo pré-tratamento com cloreto de cálcio (CaCl2), Nω-nitro-L-arginina (L-NOARG, inibidor da enzima óxido nítrico sintase - NOS), 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-ona (ODQ, inibidor da guanilato ciclase), azul de metileno (inibidor inespecífico da guanilato ciclase), tetraetilamônio (TEA; bloqueador de diferentes tipos de canais de potássio, inclusive os dependentes de voltagem), apamina (bloqueador de canais de potássio de baixa condutância ativados por cálcio) e caribidotoxina (bloqueador de canais de potássio de alta condutância ativados por cálcio), mas não foi significativamente revertida pelo pré-tratamento dos animais com glibenclamida (bloqueador de canais de K+ dependente de ATP) e com o inativador da proteína Gi/o (toxina pertussis). O tratamento oral com disseleneto de difenila reduziu a alodínia mecânica induzida pela ligadura parcial de nervo ciático (dor neuropática) e pela injeção i.pl. de FCA (dor inflamatória crônica) e preveniu a hiperalgesia térmica induzida pela BK, prostaglandina E2 (PGE2), glutamato e NMDA. De acordo com o presente trabalho pode-se sugerir que os mecanismos responsáveis pela ação antinociceptiva causada pelo disseleneto de difenila em camundongos envolvem a participação da via do óxido nítrico/ guanosina monofosfato cíclica (GMPc) /canais Ca2+ e K+, inibição da PKC e PKA, além da participação dos sistemas glutamatérgicos, peptidérgicos e vanilóides.Conselho Nacional de Desenvolvimento Científico e Tecnológicoapplication/pdfporUniversidade Federal de Santa MariaPrograma de Pós-Graduação em Ciências Biológicas: Bioquímica ToxicológicaUFSMBRBioquímicaDisseleneto de difenilaSelênioDor agudaDor crônicaNocicepçãoInflamaçãoDiphenyl diselenideSeleniumAcute painChronic painNociceptionInflammationCNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICAEstudos dos mecanismos envolvidos na ação antinociceptiva causada pelo disseleneto de difenila em camundongosStudies of mechanisms involved in the antinociceptive action caused by diphenyl diselenide in miceinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisZeni, Gilson Rogériohttp://lattes.cnpq.br/2355575631197937Nogueira, Cristina Waynehttp://lattes.cnpq.br/2877042401245169Soares, Félix Alexandre Antuneshttp://lattes.cnpq.br/8752453650114092Campos, Maria Marthahttp://lattes.cnpq.br/3601505933558375Souza, Diogo Onofre Gomes dehttp://lattes.cnpq.br/9534019126486839Rocha, João Batista Teixeira dahttp://lattes.cnpq.br/3935055744673018http://lattes.cnpq.br/1480751214999787Savegnago, Lucielli200800000002400500300300500300300500b21a898a-0ab0-4f33-b980-2b55ef590b94d471d357-47c3-4abb-a6d1-6b8e0deed9b5c2b1a64f-5f22-4779-9732-0c543f42b42d97b2e117-480f-4e1c-a62b-9dab79cb9fd3537e3eaf-551e-4f16-98f4-47af06add1da8600ecd2-5c52-443a-ae1a-771f986e643e19b305d5-beed-4822-a095-c2a70a1006e5info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações do UFSMinstname:Universidade Federal de Santa Maria (UFSM)instacron:UFSMORIGINALLUCIELLI SAVEGNAGO.pdfapplication/pdf2076955http://repositorio.ufsm.br/bitstream/1/4390/1/LUCIELLI%20SAVEGNAGO.pdf7e9d18d405cd4a5cd45eddce1bc1eb97MD511/43902023-02-22 14:24:59.883oai:repositorio.ufsm.br:1/4390Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufsm.br/ONGhttps://repositorio.ufsm.br/oai/requestatendimento.sib@ufsm.br||tedebc@gmail.comopendoar:2023-02-22T17:24:59Biblioteca Digital de Teses e Dissertações do UFSM - Universidade Federal de Santa Maria (UFSM)false
dc.title.por.fl_str_mv Estudos dos mecanismos envolvidos na ação antinociceptiva causada pelo disseleneto de difenila em camundongos
dc.title.alternative.eng.fl_str_mv Studies of mechanisms involved in the antinociceptive action caused by diphenyl diselenide in mice
title Estudos dos mecanismos envolvidos na ação antinociceptiva causada pelo disseleneto de difenila em camundongos
spellingShingle Estudos dos mecanismos envolvidos na ação antinociceptiva causada pelo disseleneto de difenila em camundongos
Savegnago, Lucielli
Disseleneto de difenila
Selênio
Dor aguda
Dor crônica
Nocicepção
Inflamação
Diphenyl diselenide
Selenium
Acute pain
Chronic pain
Nociception
Inflammation
CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA
title_short Estudos dos mecanismos envolvidos na ação antinociceptiva causada pelo disseleneto de difenila em camundongos
title_full Estudos dos mecanismos envolvidos na ação antinociceptiva causada pelo disseleneto de difenila em camundongos
title_fullStr Estudos dos mecanismos envolvidos na ação antinociceptiva causada pelo disseleneto de difenila em camundongos
title_full_unstemmed Estudos dos mecanismos envolvidos na ação antinociceptiva causada pelo disseleneto de difenila em camundongos
title_sort Estudos dos mecanismos envolvidos na ação antinociceptiva causada pelo disseleneto de difenila em camundongos
author Savegnago, Lucielli
author_facet Savegnago, Lucielli
author_role author
dc.contributor.advisor1.fl_str_mv Zeni, Gilson Rogério
dc.contributor.advisor1Lattes.fl_str_mv http://lattes.cnpq.br/2355575631197937
dc.contributor.advisor-co1.fl_str_mv Nogueira, Cristina Wayne
dc.contributor.advisor-co1Lattes.fl_str_mv http://lattes.cnpq.br/2877042401245169
dc.contributor.referee1.fl_str_mv Soares, Félix Alexandre Antunes
dc.contributor.referee1Lattes.fl_str_mv http://lattes.cnpq.br/8752453650114092
dc.contributor.referee2.fl_str_mv Campos, Maria Martha
dc.contributor.referee2Lattes.fl_str_mv http://lattes.cnpq.br/3601505933558375
dc.contributor.referee3.fl_str_mv Souza, Diogo Onofre Gomes de
dc.contributor.referee3Lattes.fl_str_mv http://lattes.cnpq.br/9534019126486839
dc.contributor.referee4.fl_str_mv Rocha, João Batista Teixeira da
dc.contributor.referee4Lattes.fl_str_mv http://lattes.cnpq.br/3935055744673018
dc.contributor.authorLattes.fl_str_mv http://lattes.cnpq.br/1480751214999787
dc.contributor.author.fl_str_mv Savegnago, Lucielli
contributor_str_mv Zeni, Gilson Rogério
Nogueira, Cristina Wayne
Soares, Félix Alexandre Antunes
Campos, Maria Martha
Souza, Diogo Onofre Gomes de
Rocha, João Batista Teixeira da
dc.subject.por.fl_str_mv Disseleneto de difenila
Selênio
Dor aguda
Dor crônica
Nocicepção
Inflamação
topic Disseleneto de difenila
Selênio
Dor aguda
Dor crônica
Nocicepção
Inflamação
Diphenyl diselenide
Selenium
Acute pain
Chronic pain
Nociception
Inflammation
CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA
dc.subject.eng.fl_str_mv Diphenyl diselenide
Selenium
Acute pain
Chronic pain
Nociception
Inflammation
dc.subject.cnpq.fl_str_mv CNPQ::CIENCIAS BIOLOGICAS::BIOQUIMICA
description The interest in organoselenium biochemistry and pharmacology has increased in the last two decades due to a variety of organoselenium compounds that possess biological activity. Accordingly, diphenyl diselenide, a simple diaryl diselenide, is known as a safety drug when administered acutely to mice at doses that have antiinflammatory and antinociceptive activities. Therefore, the research of the mechanisms by which this compound exerts its effects is extremely important for the therapeutic application. Based on the considerations above, the aims of the present study were to evaluate the acute toxicity induced by diphenyl diselenide in mice using oral route of administration with the purpose of offering safety in the use of this compound and to verify the antinociceptive and antiinflammatory activities caused by diphenyl diselenide as well as its mechanisms of action. Diphenyl diselenide administered orally produced minor toxicological effects which were evidenced by the index of mortality (lethal-dose > 312 mg/kg). Although diphenyl diselenide did not provide evidence for renal or hepatic toxicity, the body weight gain in mice exposed to this compound was reduced, which might indicate systemic toxicity. The oral administration (p.o.) of diphenyl diselenide inhibited acetic acid-induced abdominal constriction as well as capsaicin-, glutamate- bradykinin (BK)- phorbol myristate acetate (PMA)- and formalin induced nociception and caused a significant increase in tail-immersion response latency time. In addition, diphenyl diselenide co-injected intraplantarly (i.pl.) in association with glutamate induced a significant reduction of the licking and in the paw oedema formation induced by glutamate. The local pretreatment of mice with L-arginine and dithiothreitol (DTT; i.pl.) restored local antinociception caused by diphenyl diselenide when analyzed against glutamateinduced nociception. Moreover, diphenyl diselenide, given orally, caused significant inhibition of the biting behavior induced by intrathecal (i.t.) injection of glutamate, Nmethyl-D-aspartate (NMDA), substance P (SP), interleukin 1b (IL-1b), tumor necrosis factor-a (TNF-a), BK and capsaicin, but completely failed to affect the nociception induced by α-amino-3-hydroxy-5-mehtyl-4-isoxazolepropionic acid (AMPA), kainate and (±)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (trans-ACPD). The antinociceptive effect caused by diphenyl diselenide in the formalin test was reversed by i.t. injection of several K+ channel blockers such as apamin and charybdotoxin (large- and small-conductance Ca2+- activated K+ channel inhibitors, respectively), tetraethylammonium (TEA, non-selective voltage-dependent K+ channel inhibitor), but not glibenclamide (ATP-sensitive K+ channel inhibitor). Injection of mice with inhibitor of nitric oxide (NO) synthase (Nω-nitro-L-arginine; L-NOARG), guanylyl cyclase inhibitors (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one - ODQ; and methylene blue) and calcium chloride (CaCl2) significantly blocked the antinociceptive effect caused by diphenyl diselenide when assessed on the formalin test. In contrast, i.t. injection of pertussis toxin, an inactivator of Gi/0 protein, did not antagonize the antinociceptive action caused by diphenyl diselenide in the formalin test. Diphenyl diselenide increased nociceptive threshold in mechanical allodynia induced by both partial sciatic nerve ligation (neuropathic pain) and ACF i.pl. injection (inflammatory chronic pain) as well as attenuated acute thermal hyperalgesia induced by i.t. injection of glutamate, NMDA, BK and prostaglandin E2 (PGE2). Together these results suggested the participation of nitric oxide/cyclic GMP/Ca2+ and K+ channel, pathways, inhibition PKA e PKC, as well as glutamatergic, peptidergic and vanilloid systems in the antinociceptive action caused by diphenyl diselenide in mice.
publishDate 2007
dc.date.issued.fl_str_mv 2007-08-01
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dc.identifier.citation.fl_str_mv SAVEGNAGO, Lucielli. Studies of mechanisms involved in the antinociceptive action caused by diphenyl diselenide in mice. 2007. 172 f. Tese (Doutorado em Bioquímica) - Universidade Federal de Santa Maria, Santa Maria, 2007.
dc.identifier.uri.fl_str_mv http://repositorio.ufsm.br/handle/1/4390
identifier_str_mv SAVEGNAGO, Lucielli. Studies of mechanisms involved in the antinociceptive action caused by diphenyl diselenide in mice. 2007. 172 f. Tese (Doutorado em Bioquímica) - Universidade Federal de Santa Maria, Santa Maria, 2007.
url http://repositorio.ufsm.br/handle/1/4390
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