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Covalent adduct formation between the plasmalogen-derived modification product 2-chlorohexadecanal and phloretin

Hypochlorous acid added as reagent or generated by the myeloperoxidase (MPO)-H(2)O(2)-Cl(−) system oxidatively modifies brain ether-phospholipids (plasmalogens). This reaction generates a sn2-acyl-lysophospholipid and chlorinated fatty aldehydes. 2-Chlorohexadecanal (2-ClHDA), a prototypic member of...

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Autores principales: Üllen, Andreas, Nusshold, Christoph, Glasnov, Toma, Saf, Robert, Cantillo, David, Eibinger, Gerald, Reicher, Helga, Fauler, Günter, Bernhart, Eva, Hallstrom, Seth, Kogelnik, Nora, Zangger, Klaus, Oliver Kappe, C., Malle, Ernst, Sattler, Wolfgang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321883/
https://www.ncbi.nlm.nih.gov/pubmed/25576489
http://dx.doi.org/10.1016/j.bcp.2014.12.017
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author Üllen, Andreas
Nusshold, Christoph
Glasnov, Toma
Saf, Robert
Cantillo, David
Eibinger, Gerald
Reicher, Helga
Fauler, Günter
Bernhart, Eva
Hallstrom, Seth
Kogelnik, Nora
Zangger, Klaus
Oliver Kappe, C.
Malle, Ernst
Sattler, Wolfgang
author_facet Üllen, Andreas
Nusshold, Christoph
Glasnov, Toma
Saf, Robert
Cantillo, David
Eibinger, Gerald
Reicher, Helga
Fauler, Günter
Bernhart, Eva
Hallstrom, Seth
Kogelnik, Nora
Zangger, Klaus
Oliver Kappe, C.
Malle, Ernst
Sattler, Wolfgang
author_sort Üllen, Andreas
collection PubMed
description Hypochlorous acid added as reagent or generated by the myeloperoxidase (MPO)-H(2)O(2)-Cl(−) system oxidatively modifies brain ether-phospholipids (plasmalogens). This reaction generates a sn2-acyl-lysophospholipid and chlorinated fatty aldehydes. 2-Chlorohexadecanal (2-ClHDA), a prototypic member of chlorinated long-chain fatty aldehydes, has potent neurotoxic potential by inflicting blood–brain barrier (BBB) damage. During earlier studies we could show that the dihydrochalcone-type polyphenol phloretin attenuated 2-ClHDA-induced BBB dysfunction. To clarify the underlying mechanism(s) we now investigated the possibility of covalent adduct formation between 2-ClHDA and phloretin. Coincubation of 2-ClHDA and phloretin in phosphatidylcholine liposomes revealed a half-life of 2-ClHDA of approx. 120 min, decaying at a rate of 5.9 × 10(−3) min(−1). NMR studies and enthalpy calculations suggested that 2-ClHDA-phloretin adduct formation occurs via electrophilic aromatic substitution followed by hemiacetal formation on the A-ring of phloretin. Adduct characterization by high-resolution mass spectroscopy confirmed these results. In contrast to 2-ClHDA, the covalent 2-ClHDA-phloretin adduct was without adverse effects on MTT reduction (an indicator for metabolic activity), cellular adenine nucleotide content, and barrier function of brain microvascular endothelial cells (BMVEC). Of note, 2-ClHDA-phloretin adduct formation was also observed in BMVEC cultures. Intraperitoneal application and subsequent GC–MS analysis of brain lipid extracts revealed that phloretin is able to penetrate the BBB of C57BL/6J mice. Data of the present study indicate that phloretin scavenges 2-ClHDA, thereby attenuating 2-ClHDA-mediated brain endothelial cell dysfunction. We here identify a detoxification pathway for a prototypic chlorinated fatty aldehyde (generated via the MPO axis) that compromises BBB function in vitro and in vivo.
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spelling pubmed-43218832015-02-15 Covalent adduct formation between the plasmalogen-derived modification product 2-chlorohexadecanal and phloretin Üllen, Andreas Nusshold, Christoph Glasnov, Toma Saf, Robert Cantillo, David Eibinger, Gerald Reicher, Helga Fauler, Günter Bernhart, Eva Hallstrom, Seth Kogelnik, Nora Zangger, Klaus Oliver Kappe, C. Malle, Ernst Sattler, Wolfgang Biochem Pharmacol Article Hypochlorous acid added as reagent or generated by the myeloperoxidase (MPO)-H(2)O(2)-Cl(−) system oxidatively modifies brain ether-phospholipids (plasmalogens). This reaction generates a sn2-acyl-lysophospholipid and chlorinated fatty aldehydes. 2-Chlorohexadecanal (2-ClHDA), a prototypic member of chlorinated long-chain fatty aldehydes, has potent neurotoxic potential by inflicting blood–brain barrier (BBB) damage. During earlier studies we could show that the dihydrochalcone-type polyphenol phloretin attenuated 2-ClHDA-induced BBB dysfunction. To clarify the underlying mechanism(s) we now investigated the possibility of covalent adduct formation between 2-ClHDA and phloretin. Coincubation of 2-ClHDA and phloretin in phosphatidylcholine liposomes revealed a half-life of 2-ClHDA of approx. 120 min, decaying at a rate of 5.9 × 10(−3) min(−1). NMR studies and enthalpy calculations suggested that 2-ClHDA-phloretin adduct formation occurs via electrophilic aromatic substitution followed by hemiacetal formation on the A-ring of phloretin. Adduct characterization by high-resolution mass spectroscopy confirmed these results. In contrast to 2-ClHDA, the covalent 2-ClHDA-phloretin adduct was without adverse effects on MTT reduction (an indicator for metabolic activity), cellular adenine nucleotide content, and barrier function of brain microvascular endothelial cells (BMVEC). Of note, 2-ClHDA-phloretin adduct formation was also observed in BMVEC cultures. Intraperitoneal application and subsequent GC–MS analysis of brain lipid extracts revealed that phloretin is able to penetrate the BBB of C57BL/6J mice. Data of the present study indicate that phloretin scavenges 2-ClHDA, thereby attenuating 2-ClHDA-mediated brain endothelial cell dysfunction. We here identify a detoxification pathway for a prototypic chlorinated fatty aldehyde (generated via the MPO axis) that compromises BBB function in vitro and in vivo. Elsevier Science 2015-02-15 /pmc/articles/PMC4321883/ /pubmed/25576489 http://dx.doi.org/10.1016/j.bcp.2014.12.017 Text en © 2015 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Üllen, Andreas
Nusshold, Christoph
Glasnov, Toma
Saf, Robert
Cantillo, David
Eibinger, Gerald
Reicher, Helga
Fauler, Günter
Bernhart, Eva
Hallstrom, Seth
Kogelnik, Nora
Zangger, Klaus
Oliver Kappe, C.
Malle, Ernst
Sattler, Wolfgang
Covalent adduct formation between the plasmalogen-derived modification product 2-chlorohexadecanal and phloretin
title Covalent adduct formation between the plasmalogen-derived modification product 2-chlorohexadecanal and phloretin
title_full Covalent adduct formation between the plasmalogen-derived modification product 2-chlorohexadecanal and phloretin
title_fullStr Covalent adduct formation between the plasmalogen-derived modification product 2-chlorohexadecanal and phloretin
title_full_unstemmed Covalent adduct formation between the plasmalogen-derived modification product 2-chlorohexadecanal and phloretin
title_short Covalent adduct formation between the plasmalogen-derived modification product 2-chlorohexadecanal and phloretin
title_sort covalent adduct formation between the plasmalogen-derived modification product 2-chlorohexadecanal and phloretin
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4321883/
https://www.ncbi.nlm.nih.gov/pubmed/25576489
http://dx.doi.org/10.1016/j.bcp.2014.12.017
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