title: Therapies targeting lipid peroxidation in traumatic brain injury.
abstract: Lipid peroxidation can be broadly defined as the process of inserting a hydroperoxy group into a lipid. Polyunsaturated fatty acids present in the phospholipids are often the targets for peroxidation. Phospholipids are indispensable for normal structure of membranes. The other important function of phospholipids stems from their role as a source of lipid mediators - oxygenated free fatty acids that are derived from lipid peroxidation. In the CNS, excessive accumulation of either oxidized phospholipids or oxygenated free fatty acids may be associated with damage occurring during acute brain injury and subsequent inflammatory responses. There is a growing body of evidence that lipid peroxidation occurs after severe traumatic brain injury in humans and correlates with the injury severity and mortality. Identification of the products and sources of lipid peroxidation and its enzymatic or non-enzymatic nature is essential for the design of mechanism-based therapies. Recent progress in mass spectrometry-based lipidomics/oxidative lipidomics offers remarkable opportunities for quantitative characterization of lipid peroxidation products, providing guidance for targeted development of specific therapeutic modalities. In this review, we critically evaluate previous attempts to use non-specific antioxidants as neuroprotectors and emphasize new approaches based on recent breakthroughs in understanding of enzymatic mechanisms of lipid peroxidation associated with specific death pathways, particularly apoptosis. We also emphasize the role of different phospholipases (calcium-dependent and -independent) in hydrolysis of peroxidized phospholipids and generation of pro- and anti-inflammatory lipid mediators. This article is part of a Special Issue entitled SI:Brain injury and recovery.
authors.affiliation: Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Tamil Selvan
authors.initials: TS
authors.lastname: Anthonymuthu
authors.affiliation: Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15260, USA.
authors.forename: Elizabeth Megan
authors.initials: EM
authors.lastname: Kenny
authors.affiliation: Department of Critical Care Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Center for Free Radical and Antioxidant Health, University of Pittsburgh, Pittsburgh, PA 15219, USA; Safar Center for Resuscitation Research, University of Pittsburgh, Pittsburgh, PA 15260, USA; Childrens׳s Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, PA 15224, USA. Electronic address: bayihx@ccm.upmc.edu.
authors.forename: Hülya
authors.initials: H
authors.lastname: Bayır
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use*; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D018696:Neuroprotective Agents
keywords: Cardiolipin; Cyclooxygenase; Cytochrome c; Glutathione; Lipoxygenase; Phospholipase A2