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Involvement of Platelet-Activating Factor in Neurological Disorders

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Metabolism and Functions of Bioactive Ether Lipids in the Brain

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Platelet-activating factor (PAF) is a potent proinflammatory lipid mediator that is not stored, but synthesized by activated neural cells (neurons, astrocytes, oligodendrocytes, and microglial cells) as well as by nonneural cells (platelets, inflammatory, and endothelial cells) on demand by remodeling and de novo synthesis pathways. PAF receptors (PAF-Rs) are widely distributed in different brain regions and are present on the cell surface as well as in intracellular membrane compartments. In normal brain, levels of PAF are low, but levels of lyso-PAF are quite high. Thus levels of PAF in the hippocampus are higher than in cerebellum and cortex. These observations suggest that PAF is present in its inactive form in the brain tissue (Tiberghien et al., 1991). Concentration of PAF decreases with age (Tokumura et al., 1992). Under normal conditions, the synthesis of PAF in brain occurs through de novo synthesis. Normally, de novo synthesis is not influenced by the external stimulus. In response to PAF-R stimulation, injury, chemoelectroconvulsion and oxidative stress, the remodeling pathway is activated in neural and nonneural cells. Treatment of neural or nonneural cells with neurotransmitters such as dopamine and acetylcholine stimulates PAF synthesis in a calcium-dependent manner (Sogos et al., 1990). PAF is also synthesized by neurons and glial cells following stimulation with glutamate. PAF synthesis requires glutamate-mediated stimulation of NMDA receptors and subsequent elevation of intracellular calcium ions.

Microglia, which express functional PAF-Rs to a high level show a marked chemotactic response to PAF. Microglia derived from PAF-receptor-deficient mice do not show chemotactic response (Aihara et al., 2000). Thus, PAF functions as a key messenger in neuron–microglial interactions. PAF-Rs generate specific signals that are transduced by downstream effector and pathways, which may be specific to each brain cell type. Although the synthesis and release of PAF under pathological conditions in the brain has been recognized, the relative contribution of various neural and nonneural cell types for the synthesis of PAF remains unknown. Furthermore, target cells and brain regions for PAF action have not been fully identified.

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(2008). Involvement of Platelet-Activating Factor in Neurological Disorders. In: Metabolism and Functions of Bioactive Ether Lipids in the Brain. Springer, New York, NY. https://doi.org/10.1007/978-0-387-77401-5_10

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