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Previous issue date: 2014-01-24 / Spinal voltage-gated calcium channels (VGCC) are pivotal regulators of painful and inflammatory alterations, representing attractive therapeutic targets. We examined the effects of epidural administration of the selective P/Q- and N-type VGCC blockers Tx3-3 and Phα1β, respectively, isolated from the spider P. nigriventer, on symptomatic, inflammatory and functional changes allied to cyclophosphamide (CPA)-induced hemorrhagic cystitis (HC) in mice. The effects of P. nigriventer-derived toxins were compared to those displayed by MVIIC and MVIIA, extracted from the cone snail C. magus. HC was induced by a single intraperitoneal injection of CPA (300 mg/kg). The spinal blockage of P/Q-type VGCC by Tx3-3 and MVIIC, or N-type VGCC by Phα1β attenuated nociceptive and inflammatory events associated with HC, including bladder oxidative stress and cytokine production. Moreover, CPA produced an evident increase of bladder TRPV1 and TRPA1 mRNA expression, which was virtually reversed by all the tested toxins. Noteworthy, Phα1β strongly prevented bladder neutrophil migration, besides HC-related functional alterations. Finally, the spinal co-administration of the selective NK1 receptor antagonist CP-96345 heightened Phα1β antinociceptive effects. Our results shed new lights on the role of spinal P/Q and N-type VGCC in bladder dysfunctions, pointing out Phα1β as a promising alternative for treating complications associated to CPA-induced HC. / Os canais de c?lcio voltagem-dependentes (CCVDs), ao n?vel medular, s?o um dos principais reguladores das altera??es inflamat?rias e dolorosas, representando um interessante alvo terap?utico. Com isso, avaliamos os efeitos da administra??o intratecal dos bloqueadores seletivos dos CCVD do subtipo P/Q e N, Tx3-3 e Phα1β, respectivamente, isolados do veneno da aranha P. nigriventer, nas mudan?as sintom?ticas, inflamat?rias e funcionais, relacionadas com a cistite hemorr?gica (CH), induzido pelo quimioter?pico ciclofosfamida (CPA) em camundongos. Os efeitos dos pept?deos provenientes da aranha P. nigriventer foram comparados com os exibidos pelas toxinas MVIIC e MVIIA, obtidas do caramujo C. magus. A CH foi induzida por uma ?nica administra??o intraperitoneal de CPA (300 mg/kg). O bloqueio medular dos CCVD do subtipo P/Q atrav?s da Tx3-3 e MVIIC ou, o bloqueio dos CCVD do subtipo N pela toxina Phα1β atenuou as respostas nociceptivas e inflamat?rias associadas ? CH, incluindo estresse oxidativo e produ??o de citocinas na bexiga. Al?m disso, a CPA produziu um aumento evidente na express?o do RNAm de TRPV1 e TRPA1 na bexiga, o qual foi virtualmente revertido por todas as toxinas. Notavelmente, a isoforma Phα1β reduziu a migra??o de neutr?filos para a bexiga, al?m de reverter as disfun??es da bexiga relacionadas ? CH. Finalmente, a co-administra??o medular do antagonista seletivo dos receptores NK1, CP-96345, com o pept?deo Phα1β, intensificou o efeito antinociceptivo do mesmo. Nossos resultados trazem novas evid?ncias da fun??o dos CCVD do subtipo P/Q e N ao n?vel medular na disfun??o da bexiga, apontando a Phα1β como uma poss?vel alternativa de tratamento para complica??es associadas ? CH, induzida por CPA.
| Identifer | oai:union.ndltd.org:IBICT/oai:tede2.pucrs.br:tede/1760 |
| Date | 24 January 2014 |
| Creators | Silva, Rodrigo Braccini Madeira da |
| Contributors | Campos, Maria Martha |
| Publisher | Pontif?cia Universidade Cat?lica do Rio Grande do Sul, Programa de P?s-Gradua??o em Medicina e Ci?ncias da Sa?de, PUCRS, BR, Faculdade de Medicina |
| Source Sets | IBICT Brazilian ETDs |
| Language | Portuguese |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, info:eu-repo/semantics/masterThesis |
| Format | application/pdf |
| Source | reponame:Biblioteca Digital de Teses e Dissertações da PUC_RS, instname:Pontifícia Universidade Católica do Rio Grande do Sul, instacron:PUC_RS |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 7620745074616285884, 500, 600, -8624664729441623247 |
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