Cyclooxygenases, lipoxygenases, and epoxygenases in CNS: Their role and involvement in neurological disorders

Abstract

Three enzyme systems, cyclooxygenases that generate prostaglandins, lipoxygenases that form hydroxy derivatives and leukotrienes, and epoxygenases that give rise to epoxyeicosatrienoic products, metabolize arachidonic acid after its release from neural membrane phospholipids by the action of phospholipase A₂. Lysophospholipids, the other products of phospholipase A₂ reactions, are either reacylated or metabolized to platelet-activating factor. Under normal conditions, these metabolites play important roles in synaptic function, cerebral blood flow regulation, apoptosis, angiogenesis, and gene expression. Increased activities of cyclooxygenases, lipoxygenases, and epoxygenases under pathological situations such as ischemia, epilepsy, Alzheimer's disease, Parkinson disease, amyotrophic lateral sclerosis, and Creutzfeldt–Jakob disease produce neuroinflammation involving vasodilation and vasoconstriction, platelet aggregation, leukocyte chemotaxis and release of cytokines, and oxidative stress. These are closely associated with the neural cell injury which occurs in these neurological conditions. The metabolic products of docosahexaenoic acid, through these enzymes, generate a new class of lipid mediators, namely docosatrienes and resolvins. These metabolites antagonize the effect of metabolites derived from arachidonic acid. Recent studies provide insight into how these arachidonic acid metabolites interact with each other and other bioactive mediators such as platelet-activating factor, endocannabinoids, and docosatrienes under normal and pathological conditions. Here, we review present knowledge of the functions of cyclooxygenases, lipoxygenases, and epoxygenases in brain and their association with neurodegenerative diseases.

Introduction

In neural membrane phospholipids, AA and docosahexaenoic acid (DHA, 22:6n-3) are exclusively located at the sn-2 position of glycerol moiety. AA is released mainly by the action of cytosolic phospholipase A₂ (cPLA₂) (Farooqui et al., 2000b), and DHA is liberated by the action of plasmalogen-selective phospholipase A₂ (PlsEtn-PLA₂) (Hirashima et al., 1992). Free AA and DHA are either reincorporated in neural membrane phospholipids by reacylation reactions or oxidized by several enzymic and nonenzymic mechanisms to various oxygenated metabolites with important neurochemical functions (Farooqui et al., 2000a, Farooqui et al., 2000b, Lee et al., 2004a, Rapoport, 1999, Rapoport, 2003, Rapoport et al., 2001). Thus, cyclooxygenases (COX), lipoxygenases (LOX), and epoxygenases (EPOX) metabolize AA to prostaglandins, thromboxanes, leukotrienes, and epoxyeicosatrienoic acid, respectively. Eicosanoids is the collective name for these metabolites (Fig. 1).

Neurons, astrocytes, cerebral vascular endothelial cells, and cerebrospinal fluid contain numerous eicosanoids (O'Banion, 1999, O'Banion and Olschowka, 1999, Schaad et al., 1991, Shimizu and Wolfe, 1990, Simmons et al., 2004, Toda and Okamura, 1993, Vane et al., 1998, Vila, 2004, Warner et al., 2004, Werz, 2002, Wolfe, 1982). They play important roles, not only in regulating signal transduction and gene transcription processes, but also in inducing and maintaining the acute inflammatory responses (Wolfe and Horrocks, 1994). In contrast, COX and LOX metabolize DHA to resolvins, docosatrienes, and neuroprotectins. Docosanoids is the collective name for these metabolites. They not only antagonize the effects of eicosanoids (Fig. 1), but also modulate leukocyte trafficking as well as downregulating expression of cytokines (Hong et al., 2003, Marcheselli et al., 2003). Neural and non-neural tissues express several different isoforms of PLA₂, COX, and LOX under normal or stimulated situations (Kis et al., 2003, Kis et al., 2004, Kolko et al., 2005, Shaftel et al., 2003, Snipes et al., 2005). How the isoforms of PLA₂, COX, and LOX enzymes interact with each other remains to be elucidated. Cross talk between cPLA₂ and sPLA₂ for prostaglandin synthesis has been reported to occur in macrophages (Shinohara et al., 1999). Eicosanoid synthesis through COX and LOX enzymes may involve different AA substrate pools and may be coupled to distinct PLA₂ isoforms at different cellular and subcellular levels (Farooqui et al., in press, Ueno et al., 2001).

Another product of a PLA₂ catalyzed reaction, 1-alkyl-2-lyso-sn-glycero-3-phosphocholine, is the immediate precursor for platelet-activating factor (PAF), a potent inflammatory mediator. Besides inflammation in brain tissue, PAF modulates transcription factors and gene expression and is involved in stimulation and modulation of PLA₂, PLC, and PLD and COX activities.

In addition to the abovementioned lipid mediators, COX, LOX, and EPOX-catalyzed reactions also produce reactive oxygen species (ROS). ROS include oxygen free radicals (superoxide radicals, hydroxyl, and alkoxyl radicals) and peroxides (hydrogen peroxide and lipid hydroperoxide). At low levels, ROS function as signaling intermediates in the regulation of fundamental cell activities such as growth and adaptation responses. At higher concentration, ROS contribute to neural membrane damage when the balance between reducing and oxidizing (redox) forces shifts toward oxidative stress (Fig. 1). The other biological targets of ROS may be membrane proteins, unsaturated lipids, and DNA (Berlett et al., 1997). The reaction between ROS and proteins or unsaturated lipids in the plasma membrane leads to a chemical cross-linking of membrane proteins and lipids and a reduction in membrane unsaturation. The depletion of unsaturation in membrane lipids is associated with decreased membrane fluidity and decreased activity of membrane-bound enzymes, ion channels, and receptors (Ray et al., 1994).

Nonenzymic peroxidation of AA and DHA also results in the generation of 4-hydroxynonenals (4-HNE) and 4-hydroxyhexenal (4-HHE), respectively. These reactive aldehydes are important mediators of neural cell damage because of their ability to covalently modify biomolecules that can disrupt important cellular function (Esterbauer et al., 1991, Farooqui and Horrocks, in press). Finally, free-radical-mediated nonenzymic oxidation of AA and DHA produces isoprostanes (Roberts et al., 2005) and neuroprostanes (Bazan, 2005) respectively. These mediators are reliable indices of oxidative stress in vivo. This commentary has two purposes. One is to summarize studies on the multiplicity, properties, regulation, and roles of COX, LOX, and EPOX in brain tissue. The other is to present information on their activities in neurological disorders to a broader audience of neuroscientists with the hope that this discussion would initiate more studies on the importance of COX, LOX, EPOX, and their lipid mediators in neurological disorders. The inhibition of COX, LOX, and EPOX activities may provide an attractive approach for designing novel drugs for the treatment of inflammation and oxidative stress associated with neurological disorders.