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dc.typeArtigo de periódicopt_BR
dc.titleInvolvement Of Ampk, Ik Beta Alpha-nf Kappa B And Enos In The Sildenafil Anti-inflammatory Mechanism In A Demyelination Modelpt_BR
dc.contributor.authorSantana Nunespt_BR
dc.contributor.authorAna Karolina; Raposopt_BR
dc.contributor.authorCatarina; Santos Rochapt_BR
dc.contributor.authorSura Wanessa; de Sousa Barbosapt_BR
dc.contributor.authorKarla Patricia; de Almeida Lunapt_BR
dc.contributor.authorRayana Leal; da Cruz-Hoeflingpt_BR
dc.contributor.authorMaria Alice; Peixotopt_BR
dc.contributor.authorChristina Alvespt_BR
unicamp.authorda Cruz-Hoefling, Maria Alice] State Univ Campinas UNICAMP, Inst Biol, Dept Biochem & Tissue Biol, Campinas, SP, Brazilpt_BR[Santana Nunes, Ana Karolinapt Rocha, Sura Wanessapt Sousa Barbosa, Karla Patriciapt Almeida Luna, Rayana Lealpt, Christina Alves] Aggeu Magalhaes Res Ctr CPqAM, Lab Ultrastruct, BR-50670420 Recife, PE, Brazilpt[Santana Nunes, Ana Karolinapt Rocha, Sura Wanessa] Univ Fed Pernambuco, Recife, PE, Brazilpt[Raposo, Catarinapt[Raposo, Catarina] Univ Estadual Paulista Julio de Mesquita Filho UN, Sch Dent, Dept Morphol, Lab Histol & Embryol, Araraquara, SP, Brazilpt
dc.subjectActivated Protein-kinasept_BR
dc.subjectExperimental Autoimmune Encephalomyelitispt_BR
dc.subjectFunctional Recoverypt_BR
dc.description.abstractSildenafil (Viagra (R)) has recently been found to have a neuroprotective effect, which occurs through the inhibition of inflammation and demyelination in the cerebellum. However, the mechanism of action of sildenafil remains unknown. AMPK, the regulatory protein of the lipid and glucose metabolism, plays a protective role by activating the eNOS enzyme. The production of a nanomolar concentration of NO by eNOS has an anti-inflammatory effect through the cGMP signaling pathway and plays an important role in the regulation of the nuclear transcription factor (NFkB), preventing the expression of inflammatory genes. The present study investigated whether AMPK-eNOS-NO-cGMP-I kappa beta alpha-NFkB is involved in the mechanism of action of sildenafil in a cuprizone-demyelination model. Neuroinflammation and demyelination induced by cuprizone in rodents have been widely used as a model of MS. In the present study, five male C57BL/6 mice (7-10 weeks old) were used. Over a four week period, the groups received: cuprizone (CPZ) 0.2% mixed in feed; CPZ in the diet, combined with the administration of sildenafil (Viagra (R), Pfizer, 25 mg/kg) orally in drinking water, starting concurrently (sild-T0) or 15 days (sild-T15) after the start of CPZ. Control animals received pure food and water. The cerebella of the mice were dissected and processed for immunohistochemistry, immunofluorescence (frozen), western blotting and dosage of cytokines (Elisa). CPZ induced an increase in the expression of GFAP, IL-1 beta TNF-alpha, total NFkB and inactive AMPK, and prompt microglia activation. CPZ also induced a reduction of IK beta alpha. The administration of sildenafil reduced the expression of the proinflammatory cytokines IL-1 beta and TNF-alpha and increased the expression of the anti-inflammatory cytokine IL-10. In addition, the administration of sildenafil reduced expression of GFAP, NFkB, inactive AMPK and iNOS, and increased IK beta alpha. Interestingly, sildenafil also reduced levels of NGF. In general, the sild-T0 group was more effective than sild-T15 in improving clinical status and promoting the control of neuroinflammation. The present study offers evidence that sildenafil has anti-inflammatory and neuroprotective effects, which are probably achieved through modulation of AMPK-IK beta alpha-NF kappa B signaling. In addition, eNOS may play a role in the sildenafil neuroprotective mechanism, contributing to the activation of AMPK. However, other pathways such as MAPK-NFkB and the downstream proteins AMPK (AMPK-SIRT1-NF kappa B) should also be further investigated. An understanding of these mechanisms of action is critical for the clinical use of sildenafil to control neuroinflammation in neurodegenerative diseases such as MS. (C) 2015 Elsevier B.V. All rights reserved.en
dc.relation.ispartofBRAIN RESEARCHpt_BR
dc.identifier.citationInvolvement Of Ampk, Ik Beta Alpha-nf Kappa B And Enos In The Sildenafil Anti-inflammatory Mechanism In A Demyelination Model. Elsevier Science Bv, v. 1627, p. 119-133 Nov-2015.pt_BR
dc.description.sponsorshipFACEPE [AMD-0094-2.00/1]pt_BR
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)pt_BR
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)pt_BR
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)pt_BR
dc.description.sponsorship1Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)pt_BR
dc.description.sponsorship1Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)pt_BR
dc.description.sponsorship1Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)pt_BR
dc.description.sponsordocumentnumberFAPESP [2011/08005-6]pt
dc.description.provenanceMade available in DSpace on 2016-06-07T13:19:10Z (GMT). No. of bitstreams: 1 wos_000366228400012.pdf: 3361201 bytes, checksum: 476fd2b2d7395b57a0337bdb480fd086 (MD5) Previous issue date: 2015en
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