The anti-inflammatory action of the analgesic kyotorphin neuropeptide derivatives: Insights of a lipid-mediated mechanism

Recently, a designed class of efficient analgesic drugs derived from an endogenous neuropeptide, kyotorphin (KTP, Tyr-Arg) combining C-terminal amidation (KTP-NH2) and N-terminal conjugation to ibuprofen (Ib), IbKTP-NH2, was developed. The Ib moiety is an enhancer of KTP-NH2 analgesic action. In the...

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Autores: Conceição, Katia, Magalhães, Pedro R., Campos, Sara R. R., Domingues, Marco M., Ramu, Vasanthakumar Ganga, Michalek, Matthias, Bertani, Philippe, Baptista, António M., Heras i Corominas, Montserrat, Bardají Rodríguez, Eduard, Bechinger, Burkhard, Ferreira, Mônica Lopes, Castanho, Miguel Augusto Rico Botas
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2016
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10256/13191
Acesso em linha:http://hdl.handle.net/10256/13191
Access Level:acceso embargado
Palavra-chave:Analgèsics
Analgesics
Microcirculació
Microcirculation
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spelling The anti-inflammatory action of the analgesic kyotorphin neuropeptide derivatives: Insights of a lipid-mediated mechanismConceição, KatiaMagalhães, Pedro R.Campos, Sara R. R.Domingues, Marco M.Ramu, Vasanthakumar GangaMichalek, MatthiasBertani, PhilippeBaptista, António M.Heras i Corominas, MontserratBardají Rodríguez, EduardBechinger, BurkhardFerreira, Mônica LopesCastanho, Miguel Augusto Rico BotasAnalgèsicsAnalgesicsMicrocirculacióMicrocirculationRecently, a designed class of efficient analgesic drugs derived from an endogenous neuropeptide, kyotorphin (KTP, Tyr-Arg) combining C-terminal amidation (KTP-NH2) and N-terminal conjugation to ibuprofen (Ib), IbKTP-NH2, was developed. The Ib moiety is an enhancer of KTP-NH2 analgesic action. In the present study, we have tested the hypothesis that KTP-NH2 is an enhancer of the Ib anti-inflammatory action. Moreover, the impact of the IbKTP-NH2 conjugation on microcirculation was also evaluated by a unified approach based on intravital microscopy in the murine cremasteric muscle. Our data show that KTP-NH2 and conjugates do not cause damage on microcirculatory environment and efficiently decrease the number of leukocyte rolling induced by lipopolysaccharide (LPS). Isothermal titration calorimetry showed that the drugs bind to LPS directly thus contributing to LPS aggregation and subsequent elimination. In a parallel study, molecular dynamics simulations and NMR data showed that the IbKTP-NH2 tandem adopts a preferential "stretched" conformation in lipid bilayers and micelles, with the simulations indicating that the Ib moiety is anchored in the hydrophobic core, which explains the improved partition of IbKTP-NH2 to membranes and the permeability of lipid bilayers to this conjugate relative to KTP-NH2. The ability to bind glycolipids concomitant to the anchoring in the lipid membranes through the Ib residue explains the analgesic potency of IbKTP-NH2 given the enriched glycocalyx of the blood-brain barrier cells. Accumulation of IbKTP-NH2 in the membrane favors both direct permeation and local interaction with putative receptors as the location of the KTP-NH2 residue of IbKTP-NH2 and free KTP-NH2 in lipid membranes is the sameMarie Curie Industry-Academia Partnerships and Pathways (European Commission) is acknowledged for funding (FP7-PEOPLE-2007-3-1-IAPP. Project 230654)Springer Verlaginfoinfo2016info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10256/13191http://hdl.handle.net/10256/13191© Amino Acids, 2016, vol. 48, núm. 1, p. 307-318Articles publicats (D-Q)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)Inglésinfo:eu-repo/semantics/altIdentifier/doi/10.1007/s00726-015-2088-9info:eu-repo/semantics/altIdentifier/issn/0939-4451info:eu-repo/semantics/altIdentifier/eissn/1438-2199info:eu-repo/grantAgreement/EC/FP7/230654Tots els drets reservatsinfo:eu-repo/semantics/embargoedAccessoai:recercat.cat:10256/131912026-05-29T05:05:01Z
dc.title.none.fl_str_mv The anti-inflammatory action of the analgesic kyotorphin neuropeptide derivatives: Insights of a lipid-mediated mechanism
title The anti-inflammatory action of the analgesic kyotorphin neuropeptide derivatives: Insights of a lipid-mediated mechanism
spellingShingle The anti-inflammatory action of the analgesic kyotorphin neuropeptide derivatives: Insights of a lipid-mediated mechanism
Conceição, Katia
Analgèsics
Analgesics
Microcirculació
Microcirculation
title_short The anti-inflammatory action of the analgesic kyotorphin neuropeptide derivatives: Insights of a lipid-mediated mechanism
title_full The anti-inflammatory action of the analgesic kyotorphin neuropeptide derivatives: Insights of a lipid-mediated mechanism
title_fullStr The anti-inflammatory action of the analgesic kyotorphin neuropeptide derivatives: Insights of a lipid-mediated mechanism
title_full_unstemmed The anti-inflammatory action of the analgesic kyotorphin neuropeptide derivatives: Insights of a lipid-mediated mechanism
title_sort The anti-inflammatory action of the analgesic kyotorphin neuropeptide derivatives: Insights of a lipid-mediated mechanism
dc.creator.none.fl_str_mv Conceição, Katia
Magalhães, Pedro R.
Campos, Sara R. R.
Domingues, Marco M.
Ramu, Vasanthakumar Ganga
Michalek, Matthias
Bertani, Philippe
Baptista, António M.
Heras i Corominas, Montserrat
Bardají Rodríguez, Eduard
Bechinger, Burkhard
Ferreira, Mônica Lopes
Castanho, Miguel Augusto Rico Botas
author Conceição, Katia
author_facet Conceição, Katia
Magalhães, Pedro R.
Campos, Sara R. R.
Domingues, Marco M.
Ramu, Vasanthakumar Ganga
Michalek, Matthias
Bertani, Philippe
Baptista, António M.
Heras i Corominas, Montserrat
Bardají Rodríguez, Eduard
Bechinger, Burkhard
Ferreira, Mônica Lopes
Castanho, Miguel Augusto Rico Botas
author_role author
author2 Magalhães, Pedro R.
Campos, Sara R. R.
Domingues, Marco M.
Ramu, Vasanthakumar Ganga
Michalek, Matthias
Bertani, Philippe
Baptista, António M.
Heras i Corominas, Montserrat
Bardají Rodríguez, Eduard
Bechinger, Burkhard
Ferreira, Mônica Lopes
Castanho, Miguel Augusto Rico Botas
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Analgèsics
Analgesics
Microcirculació
Microcirculation
topic Analgèsics
Analgesics
Microcirculació
Microcirculation
description Recently, a designed class of efficient analgesic drugs derived from an endogenous neuropeptide, kyotorphin (KTP, Tyr-Arg) combining C-terminal amidation (KTP-NH2) and N-terminal conjugation to ibuprofen (Ib), IbKTP-NH2, was developed. The Ib moiety is an enhancer of KTP-NH2 analgesic action. In the present study, we have tested the hypothesis that KTP-NH2 is an enhancer of the Ib anti-inflammatory action. Moreover, the impact of the IbKTP-NH2 conjugation on microcirculation was also evaluated by a unified approach based on intravital microscopy in the murine cremasteric muscle. Our data show that KTP-NH2 and conjugates do not cause damage on microcirculatory environment and efficiently decrease the number of leukocyte rolling induced by lipopolysaccharide (LPS). Isothermal titration calorimetry showed that the drugs bind to LPS directly thus contributing to LPS aggregation and subsequent elimination. In a parallel study, molecular dynamics simulations and NMR data showed that the IbKTP-NH2 tandem adopts a preferential "stretched" conformation in lipid bilayers and micelles, with the simulations indicating that the Ib moiety is anchored in the hydrophobic core, which explains the improved partition of IbKTP-NH2 to membranes and the permeability of lipid bilayers to this conjugate relative to KTP-NH2. The ability to bind glycolipids concomitant to the anchoring in the lipid membranes through the Ib residue explains the analgesic potency of IbKTP-NH2 given the enriched glycocalyx of the blood-brain barrier cells. Accumulation of IbKTP-NH2 in the membrane favors both direct permeation and local interaction with putative receptors as the location of the KTP-NH2 residue of IbKTP-NH2 and free KTP-NH2 in lipid membranes is the same
publishDate 2016
dc.date.none.fl_str_mv 2016
info
info
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10256/13191
http://hdl.handle.net/10256/13191
url http://hdl.handle.net/10256/13191
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1007/s00726-015-2088-9
info:eu-repo/semantics/altIdentifier/issn/0939-4451
info:eu-repo/semantics/altIdentifier/eissn/1438-2199
info:eu-repo/grantAgreement/EC/FP7/230654
dc.rights.none.fl_str_mv Tots els drets reservats
info:eu-repo/semantics/embargoedAccess
rights_invalid_str_mv Tots els drets reservats
eu_rights_str_mv embargoedAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer Verlag
publisher.none.fl_str_mv Springer Verlag
dc.source.none.fl_str_mv © Amino Acids, 2016, vol. 48, núm. 1, p. 307-318
Articles publicats (D-Q)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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