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SHR Neuro Krebs Kardio Lipid Stoffw Microb
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
Doi: 10.1016/j.bcp.2014.12.017
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- Führende Autor*innen der Med Uni Graz
- Nusshold Christoph
- Sattler Wolfgang
- Üllen Andreas
- Co-Autor*innen der Med Uni Graz
- Bernhart Eva Maria
- Eibinger Gerald
- Fauler Günter
- Hallström Seth
- Hinteregger Helga
- Kogelnik Nora
- Malle Ernst
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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 (using NLM MeSH Indexing)
- Aldehydes - chemistry
- Aldehydes - metabolism
- Aldehydes - pharmacology
- Animals -
- Blood-Brain Barrier - drug effects
- Blood-Brain Barrier - metabolism
- Cells, Cultured -
- Endothelium, Vascular - drug effects
- Endothelium, Vascular - metabolism
- Male -
- Mice -
- Mice, Inbred C57BL -
- Phloretin - chemistry
- Phloretin - metabolism
- Phloretin - pharmacology
- Plasmalogens - chemistry
- Plasmalogens - metabolism
- Plasmalogens - pharmacology
- Sheep -
- Swine -
- Find related publications in this database (Keywords)
- Chlorinated fatty aldehyde
- Blood-brain barrier
- Neuroinflammation
- Myeloperoxidase
- Plasmalogens