Comparison of biochemical effects of statins and fish oil in brain: The battle of the titans

Abstract

Neural membranes are composed of glycerophospholipids, sphingolipids, cholesterol and proteins. The distribution of these lipids within the neural membrane is not random but organized. Neural membranes contain lipid rafts or microdomains that are enriched in sphingolipids and cholesterol. These rafts act as platforms for the generation of glycerophospholipid-, sphingolipid-, and cholesterol-derived second messengers, lipid mediators that are necessary for normal cellular function. Glycerophospholipid-derived lipid mediators include eicosanoids, docosanoids, lipoxins, and platelet-activating factor. Sphingolipid-derived lipid mediators include ceramides, ceramide 1-phosphates, and sphingosine 1-phosphate. Cholesterol-derived lipid mediators include 24-hydroxycholesterol, 25-hydroxycholesterol, and 7-ketocholesterol. Abnormal signal transduction processes and enhanced production of lipid mediators cause oxidative stress and inflammation. These processes are closely associated with the pathogenesis of acute neural trauma (stroke, spinal cord injury, and head injury) and neurodegenerative diseases such as Alzheimer disease. Statins, the HMG-CoA reductase inhibitors, are effective lipid lowering agents that significantly reduce risk for cardiovascular and cerebrovascular diseases. Beneficial effects of statins in neurological diseases are due to their anti-excitotoxic, antioxidant, and anti-inflammatory properties. Fish oil ω-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have similar anti-excitotoxic, antioxidant and anti-inflammatory effects in brain tissue. Thus the lipid mediators, resolvins, protectins, and neuroprotectins, derived from eicosapentaenoic acid and docosahexaenoic acid retard neuroinflammation, oxidative stress, and apoptotic cell death in brain tissue. Like statins, ingredients of fish oil inhibit generation of β-amyloid and provide protection from oxidative stress and inflammatory processes. Collective evidence suggests that antioxidant, anti-inflammatory, and anti-apoptotic properties of statins and fish oil contribute to the clinical efficacy of treating neurological disorders with statins and fish oil. We speculate that there is an overlap between neurochemical events associated with neural cell injury in stroke and neurodegenerative diseases. This commentary compares the neurochemical effects of statins with those of fish oil.

Introduction

Neural membranes contain glycerophospholipids, sphingolipids, cholesterol, and proteins. These lipids are asymmetrically distributed between the two leaflets of lipid bilayers (Ikeda et al., 2006, Yamaji-Hasegawa and Tsujimoto, 2006). Glycerophospholipids and sphingolipids contribute to the lipid asymmetry, whilst cholesterol and sphingolipids form lipid microdomains or lipid rafts (see below). Glycerophospholipids are made up of a glycerol backbone, fatty acids, phosphoric acid, and a nitrogenous base. Usually, at carbon atom 1, glycerophospholipids contain a saturated fatty acid such as palmitic acid, whereas carbon 2 is esterified with long-chain unsaturated fatty acids such as arachidonic acid (20:4 n-6 or 20:4 ω-6, AA) or docosahexaenoic acid (22:6 n-3 or 22:6 ω-3, DHA) (Farooqui et al., 2000a, Farooqui and Horrocks, 2006). In glycerophospholipids, glycerol is esterified at carbon-3 with phosphoric acid and a nitrogenous base. Among glycerophospholipids, phosphatidylcholine (PtdCho) is mainly located in the outer leaflet, whereas phosphatidylserine (PtdSer), phosphatidylethanolamine (PtdEtn), plasmenylethanolamine (PlsEtn), and phosphatidylinositol (PtdIns) are mainly located in the inner leaflet (Farooqui and Horrocks, 2007a). The binding of phospholipids to proteins is necessary for the vertical positioning and tight integration of proteins in the lipid bilayer (Palsdottir and Hunte, 2004). Phospholipid binding is stabilized by multiple noncovalent interactions between protein residues and phospholipid head groups and hydrophobic tails. Based on the correlation of glycerophospholipid head groups with membrane protein structures, distinct motifs have been identified for stabilizing interactions between the phosphodiester moieties and side chains of amino acid residues in proteins (Palsdottir and Hunte, 2004, Farooqui and Horrocks, 2006).

Sphingolipids consist of a sphingoid base, a straight-chain alcohol of 18 to 20 carbon atoms, which is normally attached to a long saturated fatty acid (usually palmitate) through an amide bond. Sphingosine contains a trans double bond between carbons C-4 and C-5 whilst dihydrosphingosine lacks this double bond. Based on their head group, sphingolipids include glycosphingolipids with a sugar as the head group, ceramide or N-acylsphingosine with no head group, and phosphosphingolipids (primarily sphingomyelin, a phosphodiester of ceramide and choline). Sphingomyelin is a major constituent of plasma membranes where it is concentrated in the outer leaflet (Vaena de Avalos et al., 2004). Sphingolipids are metabolized to ceramide and sphingosine. Exogenous application of ceramide is cytotoxic. Ceramide is metabolized to less toxic forms by glycosylation, acylation, or by catabolism to sphingosine, which is then phosphorylated to the anti-apoptotic sphingosine 1-phosphate (Farooqui et al., 2007a).

Cholesterol is a major constituent of neural membranes. It accounts for 20 to 25% of the total body cholesterol in fresh brain. The level of brain cholesterol is estimated to be 15 to 20 mg/g tissue. It plays a crucial role in membrane organization, dynamics, function, and sorting (Simons and Ikonen, 2000). Cholesterol not only serves as a precursor for the synthesis of oxysterols, steroid hormones, and lipoproteins, but regulates activities of membrane-bound enzymes, receptors, and ion channels (Simons and Ikonen, 2000). Cholesterol also modulates endocytosis and antigen expression. Dynamic clustering of cholesterol along with sphingolipids results in formation of specialized structures called microdomains or rafts. In neural membranes, raft formation occurs by self-association of sphingolipids via their long saturated hydrocarbon chains. Cholesterol condenses this packing by positioning between these hydrocarbon chains below the large head groups of the sphingolipids. These interactions lead to the formation of a less fluid, liquid ordered phase, separate from a phosphatidylcholine-rich liquid-disordered phase (Simons and Ikonen, 2000).

It is proposed that lipid rafts float within the membrane and certain groups of proteins unite within these rafts. These structures play crucial roles in neural cell functions such as signal transduction, adhesion, sorting, trafficking, and organizing bilayer constituents including receptors, enzymes, and ion channels (Simons and Ikonen, 2000, Farooqui et al., 2000a, Farooqui and Horrocks, 2006). Furthermore, some transmembrane proteins function better in a high cholesterol environment than others (Tun et al., 2002). The organization of glycerophospholipids, sphingolipids and cholesterol provides neural membranes with structural and functional integrity that facilitates appropriate interactions with integral membrane proteins. These interactions not only modulate their function through signal transduction processes but also control adaptive responses (Ivanova et al., 2004). In general, the function of the signal transduction network is to convey extracellular signals from the cell surface to the nucleus to induce a biological response at the gene level.

Modification of neural membrane cholesterol content induces alterations in membrane fluidity, lipid packing, and permeability. Collective evidence from multiple studies suggests that cross talk between ceramide, glycerophospholipid, and cholesterol signaling occurs in neural cells (Kihara and Igarashi, 2004). This controlled and coordinated signaling may not only vary significantly from one neural cell type to another but also with respect to the nature of stimulus, plus its dosage and/or duration of treatment. Thus an interplay or cross talk is necessary between lipid mediators derived from glycerophospholipids, sphingolipids, and cholesterol for neural cell proliferation, cell mobility, neurite retraction, and survival. However, high concentrations of these metabolites cause oxidative stress, membrane blebbing, and other neurochemical and morphological changes that promote neural cell death and tumor invasiveness. The cross talk between mediators derived from sphingolipids, glycerophospholipids, and cholesterol is not only necessary for maintaining the functional lipid asymmetry of lipid bilayers in plasma membranes, but also for modulating the intensity of signal transduction process associated with neural cell survival and neurodegeneration (Farooqui et al., 2000a, Farooqui et al., 2000b, Koletzko et al., 2001, Kihara and Igarashi, 2004).

Both statins and long-chain ω-3 fatty acids from fish oil inhibit HMG-CoA reductase and have similar pleiotropic and vasoprotective effects in neural and non-neural tissues (Endres, 2005, Eckert et al., 2005, Hirafuji et al., 2003, Farooqui and Horrocks, 2006, Horrocks and Farooqui, 2004). They modulate glycerophospholipid, sphingolipid, and cholesterol metabolism in neural membranes. The purpose of this review is to compare the neurochemical effects of statins and ingredients of fish oil (eicosapentaenoic and docosahexaenoic acids) on signaling processes associated with neural cell survival and death with the hope that this discussion will initiate more studies on the molecular mechanisms of their action and on the therapeutic value of statins and fish oil in neural trauma and neurodegenerative diseases.