Phospholipids, Sphingolipids, and Cholesterol-Derived Lipid Mediators and Their Role in Neurological Disorders

Abstract

Neural membranes are composed of phospholipids, sphingolipids, cholesterol, and proteins. In response to cell stimulation or injury, the metabolism of lipids generates various lipid mediators, which perform many cellular functions. Thus, phospholipids release arachidonic acid or docosahexaenoic acid from the sn-2 position of the glycerol moiety by the action of phospholipases A₂. Arachidonic acid is a precursor for prostaglandins, leukotrienes, thromboxane, and lipoxins. Among these mediators, prostaglandins, leukotrienes, and thromboxane produce neuroinflammation. In contrast, lipoxins produce anti-inflammatory and pro-resolving effects. Prostaglandins, leukotrienes, and thromboxane are also involved in cell proliferation, differentiation, blood clotting, and blood vessel permeability. In contrast, DHA-derived lipid mediators are called specialized pro-resolving lipid metabolites (SPMs). They include resolvins, protectins, and maresins. These mediators regulate immune function by producing anti-inflammatory, pro-resolving, and cell protective effects. Sphingolipid-derived metabolites are ceramide, ceramide1-phosphate, sphingosine, and sphingosine 1 phosphate. They regulate many cellular processes, including enzyme activities, cell migration and adhesion, inflammation, and immunity. Cholesterol is metabolized into hydroxycholesterols and 7-ketocholesterol, which not only disrupts membrane fluidity, but also promotes inflammation, oxidative stress, and apoptosis. These processes lead to cellular damage.

Keywords: 4-hydroxyhexanal; 4-hydroxynonal; 7-ketocholesterol; arachidonic acid; ceramide-1-phosphate; docosahexaenoic acid; hydroxycholesterol; isoprostane; leukotrienes; lipoxins; maresins; neuroprostane; phospholipids; prostaglandins; protectins; resolvins; sphingosine; sphingosine 1-phosphate; thromboxane.

Figure 1

Enzymatic and non-enzymatic metabolism of arachidonic acid. Plasma membrane (PM); N-methyl-D-aspartate receptor (NMDA-R); glutamate (Glu); phosphatidylcholine (PtdCho); lysophosphatidylcholine (Lyso-PtdCho); cytosolic phospholipase A₂ (cPLA₂); arachidonic acid (ARA); cyclooxygenase-2 (COX-2); 5-lipoxygenase (5-LOX); 15-lipoxygenase (15-LOX); platelet-activating factor (PAF); epoxyeicosatetraenoic acids (EETs); prostaglandins (PGs); leukotrienes (LTs); thromboxane (TX); lipoxins (LXs); 4-hydroxy 2-nonenal (4-HNE); cerebral blood flow (CBF); A1 (Glu); mitogen-activated protein kinase (P38); serine/threonine protein kinase (ERK).

Figure 2

Chemical structures of non-enzymatic mediators of arachidonic acid metabolism.

Figure 3

Enzymatic and non-enzymatic metabolism of docosahexaenoic acid. Plasma membrane (PM); N-methyl-D-aspartate receptor (NMDA-R); glutamate (Glu); ethanolamine plasmalogen (PlsEtn); lyso-plasmalogen (Lyso-PlsEtn); plasmalogen-specific phospholipase A2 (PlsEtn-PLA2); docosahexaenoic acid (DHA); 15-lipoxygenase (15-LOX); 4-hydroxyhexenal (4-HHE); A1 (Glu); mitogen-activated protein kinase (P38); serine/threonine protein kinase (ERK).

Figure 4

Metabolism and role of ceramide, ceramide 1-phosphate, and sphingosine 1 phosphate (S 1 P). Tumor necrosis factor-α (TNF-α tumor necrosis factor-α-receptor (TNF-R sphingomyelin (SM); sphingomyelinase (SMase); ceramide 1 phosphate (C1-P); nuclear factor-κB (NF-κB); nuclear factor-κB response element (NF-κB-RE); reactive oxygen species (ROS); tumor necrosis factor-α (TNF-α); interleukin-1β (IL-1β); interleukin-6 (IL-6); haemoxygenase (HO-1); NADPH quinine oxidoreductase (NQO-1); γ-glutamate cystein ligase (γ-GCL), and antioxidant response-element (ARE).

Figure 5

Effect of ROS on cholesterol and synthesis of 7-ketocholesterol in brain and visceral tissues. Plasma membrane (PM); N-methyl-D-aspartate receptor (NMDA-R); glutamate (Glu); phosphatidylcholine (PtdCho); lysophosphatidylcholine (Lyso-PtdCho); cytosolic phospholipase A₂ (cPLA₂); arachidonic acid (ARA); cyclooxygenase-2 (COX-2); 5-lipoxygenase (5-LOX); prostaglandins (PGs); leukotrienes (LTs); thromboxane (TX); nuclear factor-κB (NF-κB); nuclear factor-κB response element (NF-κB-RE); reactive oxygen species (ROS); 7-ketocholesterol (7-KC); tumor necrosis factor-alpha (TNF-α); interleukin 1β (IL-1β); interleukin-6 (IL-6); monocyte chemotactic protein-1 (MCP1); secretory phospholipase A₂ (sPLA₂).