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

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• 作者：Katia Conceição ; Pedro R. Magalhães ; Sara R. R. Campos ; Marco M. Domingues…
• 关键词：Kyotorphin ; Kyotorphin amide ; Ibuprofen ; Analgesia ; Microcirculation
• 刊名：Amino Acids
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：48
• 期：1
• 页码：307-318
• 全文大小：1,217 KB
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• 作者单位：Katia Conceição (1) (2) r> Pedro R. Magalhães (3) r> Sara R. R. Campos (3) r> Marco M. Domingues (1) r> Vasanthakumar G. Ramu (4) r> Matthias Michalek (5) r> Philippe Bertani (5) r> António M. Baptista (3) r> Montserrat Heras (4) r> Eduard R. Bardaji (4) r> Burkhard Bechinger (5) r> Mônica Lopes Ferreira (6) r> Miguel A. R. B. Castanho (1) r>r>1. Faculdade de Medicina de Lisboa, Instituto de Medicina Molecular, Av. Professor Egas Moniz, 1649-028, Lisbon, Portugal r> 2. Departamento de Ciência e Tecnologia, Universidade Federal de São Paulo, UNIFESP, Rua Talim, 330, São José dos Campos, Brazil r> 3. Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, 2780-157, Oeiras, Portugal r> 4. Laboratori d’Innovació en Processos i Productes de Síntesi Orgànica (LIPPSO), Departament de Química, Universitat de Girona, Campus Montilivi, 17071, Girona, Spain r> 5. UMR7177, Institut de chimie de Strasbourg, CNRS, University of Strasbourg, 67000, Strasbourg, France r> 6. Unidade de Imunorregulação, Laboratório Especial de Toxinologia Aplicada, Instituto Butantan, Av. Vital Brasil, São Paulo, 1500, Brazil r>
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Life Sciencesr>Biochemistryr>Analytical Chemistryr>Biochemical Engineeringr>Life Sciencesr>Proteomicsr>Neurobiologyr>
• 出版者：Springer Wien
• ISSN：1438-2199

文摘

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. Keywords Kyotorphin Kyotorphin amide Ibuprofen Analgesia Microcirculation