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.

Keywords: Cardiolipin; Cyclooxygenase; Cytochrome c; Glutathione; Lipoxygenase; Phospholipase A2.

Figure 1. Chain reaction of lipid peroxidation

Chain reaction of lipid peroxidation involves a three step pathway: 1) initiation - removal of a hydrogen from PUFAs to form a carbon-centered lipid radical; 2) propagation - attachment of a peroxy group to the lipid radical to form a lipid peroxyl radical. This lipid peroxyl radical initiates a new cycle by extracting a hydrogen, thereby perpetuating the peroxidation reaction; and 3) termination - disappearance of free radical by forming a non-radical such as hydroxide.

Figure 2

Reactions involved in the production of free radicals.

Figure 3. Biosynthetic pathways of specialized pro-resolving lipid mediators (SPMs)

Free fatty acids produced after the hydrolysis of phospholipids such as phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylethanolamine (PE) and phosphatidylinositol (PI) are modified by either LOX or acetylated COX to produce the hydroperoxy fatty acids. Hydroperoxy arachidonic acids are directly converted into lipoxin and epi lipoxin by the LOX enzyme, and Hydroperoxy EPA is converted into Resolvin E1, and E2. In the case of hydroperoxy DHA, further conversion to epoxy products and consequently into maresins and resolvin D1, D2 occurs.

Figure 4

Lipid mediators and their roles in inflammation

Figure 5. Lipid peroxidation mechanisms after TBI and possible therapeutic targets

Lipid peroxidation after TBI follows two main pathways: 1) Calcium-dependent pathway in which PUFAs are initially hydrolyzed from phospholipids by PLA2 and subsequently oxidized by various enzymes; 2) Calcium-independent mitochondrial pathway in which mitochondria specific phospholipid cardiolipin is oxidized by cytochrome c/H2O2 and further hydrolyzed by calcium independent PLA2 to form lipid peroxides. Inhibition or reduction of marked components or enhanced activity of marked components in lipid peroxidation pathways are possible therapeutic options after TBI.