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SHR Neuro Krebs Kardio Lipid

Üllen, A; Nusshold, C; Glasnov, T; Saf, R; Cantillo, D; Eibinger, G; Reicher, H; Fauler, G; Bernhart, E; Hallstrom, S; Kogelnik, N; Zangger, K; Oliver Kappe, C; Malle, E; Sattler, W.
Covalent adduct formation between the plasmalogen-derived modification product 2-chlorohexadecanal and phloretin.
Biochem Pharmacol. 2015; 93(4): 470-481. [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG

 

Autor/innen der Med Uni Graz:
Bernhart Eva Maria
Eibinger Gerald
Fauler Günter
Hallström Seth
Kogelnik Nora
Malle Ernst
Nusshold Christoph
Reicher Helga
Sattler Wolfgang
Üllen Andreas
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Number of Figures: 7
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Abstract:
Hypochlorous acid added as reagent or generated by the myeloperoxidase (MPO)-H2O2-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. 120min, 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. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Find related publications in this database (Keywords)
Chlorinated fatty aldehyde
Blood-brain barrier
Neuroinflammation
Myeloperoxidase
Plasmalogens
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