Lipid Mediators

Platelet-Activating Factor and Other Bioactive Lipids

A target for cerebral ischemia is phospholipids from plasma membranes of neural cells. Phospholipid molecules of membranes from neurons, glial cells, and other neural cells store a variety of lipid messengers. Receptor-mediated events, or changes in intracellular events [Ca ²⁺ ], such as those that occur during excitatory neurotransmission in activity-dependent synaptic plasticity, uncompensated oxidative stress, and other disruptors of homeostasis, activate phospholipases that catalyze the release of precursors of bioactive mediators from phospholipids. These messengers then participate in intracellular and/or intercellular signaling pathways. Accordingly, contemporary research into bioactive lipids has focused on their neurobiological significance and role in diseases.

Cerebral ischemia unsettles the tightly regulated events that control the production and accumulation of lipid messengers and their precursors, such as docosahexaenoic acid (DHA), free arachidonic acid (AA), diacylglycerol, and platelet-activating factor (PAF, 1-O-alkyl-2-acyl- sn -3-phosphocholine), under physiological conditions. Rapid activation of phospholipases, particularly of phospholipase A ₂ (PLA ₂ ), occurs at the onset of cerebral ischemia . There are a wide variety of PLA ₂ s and current investigations aim to define those affected by ischemia. For example, in addition to the role(s) of intracellular PLA ₂ s in lipid messenger formation, a low-molecular-weight secretory PLA ₂ synergizes glutamate-induced neuronal damage. Pathways leading to PLA ₂ activation/release are part of normal neuronal function, whereas ischemia-reperfusion enhances these events, overproducing PLA ₂ -derived lipid messengers (e.g., enzymatically produced AA or DHA oxygenation derivatives, nonenzymatically generated lipid peroxidation products, and other reactive oxygen species) involved in neuronal damage. Among the consequences of PLA ₂ activation by ischemia are alterations in mitochondrial function by the rapid increase in the brain free fatty acid pool size (e.g., uncoupling of oxidative phosphorylation from respiratory chain) and the generation of lipid messengers.

PAF is a very potent and short-lived lipid messenger. It is known to have a wide range of actions: as a mediator of inflammatory and immune responses, as a second messenger, and as a potent inducer of gene expression in neural systems. Thus, in addition to its acute roles, PAF can potentially mediate longer-term effects on cellular physiology and brain functions.