Phospholipid Degradation, Second Messengers and Activation of Cell Signaling Genes

Abstract

Platelet-activating factor (PAF) is one of the most potent biologically active lipids known. It is a mediator of inflammatory and immunological events at concentrations down to the picomolar range in a wide variety of cells and tissues (for a review see Braquet et al., 1987). A role for PAF in the nervous system has been suggested by the ability of seizures (Kumar et al., 1988) and certain neurotransmitters (Bussolino et al., 1986; Sogos et al., 1990) to trigger the formation of PAF in the brain and in neuronal cells. Moreover, the finding that PAF antagonists confer neuroprotection during ischemia-reperfusion injury (Panetta et al., 1987) highlights a potential physiological effect of PAF in the nervous system. PAF is undetectable in resting cells. However, seizures or cerebral ischemia rapidly activate phospholipases A₂ (Bazan, 1970) and C., resulting in the release of PAF and other short-lived second messengers. The study of the signal transduction events that control PAF synthesis is only now beginning to evolve. However, two new clues about the biological activity of PAF in the brain have been found. In presynaptic nerve terminals, PAF enhances excitatory neurotransmitter release in hippocampal neurons (Clark et al., 1991; Clark et al., 1992 a, b); and, through a pharmacologically distinct intracellular site, PAF activates transcription of immediate early genes in the brain (Marcheselli et al., 1990 a, b; Bazan et al., 1991). These novel effects could have both physiological and pathophysiological significance.