Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Uellen, A.
Myeloperoxidase-Mediated Alterations of Plasmalogen Homeostasis Induce Blood-Brain Barrier Dysfunction
[ Dissertation ] Medical University of Graz; 2011. pp. 215
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- Autor*innen der Med Uni Graz:
- Üllen Andreas
- Betreuer*innen:
- Malle Ernst
- Sattler Wolfgang
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- Abstract:
- Normal brain function depends on a delicately balanced set of remarkably diverse lipids. Consequently, short and long-term alterations in brain lipid composition during acute and chronic neuroinflammatory conditions associated with oxidative stress are casually involved in central nervous system (CNS) disorders (e.g. Alzheimer¿s disease, multiple sclerosis, Parkinson¿s disease, stroke or traumatic brain injury). Within the different cerebral lipid subclasses plasmalogens, 1-O-alk-1¿-enyl-2-acyl-sn-glycero-phospholipids, take a central role in CNS function. Plasmalogen deficiency results in severe and long-lasting developmental alterations in the brain and is linked to several neurodegenerative diseases. Among the oxidant systems contributing to the formation of reactive species, myeloperoxidase (MPO) plays a central role. After activation of phagocytes, MPO uses chloride ions and hydrogen peroxide generated from superoxide anion radicals to form hypochlorous acid (HOCl). This potent oxidant targets unsaturated lipids to form a battery of chlorinated lipotoxic compounds. Of note, due to the presence of an O-alkenyl-ether group at the sn-1 position these ether phospholipids are particularly sensitive towards HOCl-mediated modification. Therefore, the present study aimed at investigating the impact of experimentally induced neuroinflammation on MPO-mediated chlorinative stress on CNS plasmalogens. By means of an in vivo mouse model I could demonstrate that a single dose of peripherally applied endotoxin leads to cerebral plasmalogen loss. These experiments revealed that MPO-derived HOCl modifies a significant proportion of brain plasmalogens leading to the formation of highly reactive ¿-chloro fatty aldehydes (e.g. 2-ClHDA). Further studies in this murine model identified recruitment of MPO-containing neutrophils to the cerebrovasculature as a likely event contributing to blood-brain barrier (BBB) dysfunction under neuroinflammatory conditions. Using an in vitro model of the BBB I could identify molecular mechanisms/signaling pathways leading to 2-ClHDA-induced apoptosis and altered permeability properties. Of note, pharmacological modulation of these pathways resulted in partial restoration of barrier function. Also the use of natural polyphenolic compounds identified candidates with high chemical scavenging potential for MPO-derived HOCl and 2-ClHDA thereby providing significant protection against barrier dysfunction. In summary, the present study indicates that activation of the innate immune system and plasmalogen modification by MPO-derived HOCl might play a critical role in the setting of neurological disorders. A thorough understanding of the underlying signaling pathways could ultimately impact on targeted pharmacological interventions under conditions where normal function of the BBB is compromised.