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Platelet-activating factor and polyunsaturated fatty acids in cerebral ischemia or convulsions: Intracellular PAF-binding sites and activation of a fos/jun/AP-1 transcriptional signaling system

  • PAF and the Cerebral System
  • Review
  • Published:
Lipids

Abstract

Platelet-activating factor (PAF) is a lipid mediator formed in the early response of the central nervous system to ischemia or convulsions. Free polyunsaturated fatty acids and arachidonic and docosahexaenoic acids are accumulated along with PAF. Antagonists of PAF have been found to improve cerebral blood flow and partially block the rise in free fatty acids, an effect that may arise by way of inhibition of PAF receptors or stimulation of the reacylation of free fatty acids released upon insult. Three intracellular PAF-binding sites have been identified in rat cerebral cortex. These very high-affinity binding sites are inhibited by PAF antagonists, with certain antagonists exhibiting specificity for a particular binding site. This specificity indicates heterogeneity in these binding sites. Ischemia or stimulation also leads to protooncogene transcriptional activation. Here, we discuss studies with cells in culture showing that PAF promotes transcriptional activation of immediate-early genes. PAF activates the transcription of the immediate-early genesfos andjun, whose gene products are regulators of the transcription of other genes. Transcription offos is also activated by convulsion or ischemia in the central nervous system. The activation of these genes by PAF can be inhibited by PAF antagonists, and is apparently accomplished by way of an AP-1 transcription regulatory sequence in the promoter region of the target genes. Studies with deletion mutants show that PAF can also exert its activating properties by way of cyclic adenosine-3′,5′-monophosphate-(cAMP) and Ca2+-responsive elements, and suggest that PAF is involved in an interconnected network of cell signaling that may coordinate short-term and long-term responses of cells to stimulus and injury.

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Abbreviations

AGEPC:

1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine

B max :

binding sites density

cAMP:

cyclic adenosine-3′,5′-monophosphate

CNS:

central nervous system

DSE:

dyad symmetry element

FFA:

free fatty acids

GPC:

glycerophosphocholine

HIV-1:

human immunodeficiency virus-1

IC50 :

50% inhibitory concentration

K D :

rate of dissociation

K i :

inhibitor constant

LTR:

long terminal repeat

mRNA:

messenger ribonucleic acid

PAF:

platelet-activating factor

PLA2 :

phospholipase A2

PMA:

phorbol myristate acetate

PUFA:

polyunsaturated fatty acids

SRE:

serum response element

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Author notes

  1. Stephen P. Squinto

    Present address: Molecular and Cellular Biology Division, Regeneron Pharmaceuticals, Inc., Suite 10, 777 Old Saw Mill River Road, 10591, Tarrytown, NY

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Louisiana State University Medical Center School of Medicine, 2020 Gravier Street, Suite B, 70112, New Orieans, Louisiana

    Nicolas G. Bazan & Stephen P. Squinto

  2. Department of Ophthalmology, Louisiana State University Medical Center School of Medicine, 2020 Gravier Street, Suite B, 70112, New Orieans, Louisiana

    Nicolas G. Bazan & Victor L. Marcheselli

  3. Department of Surgery, Louisiana State University Medical Center School of Medicine, 2020 Gravier Street, Suite B, 70112, New Orieans, Louisiana

    Thomas Panetta

  4. Department of Neuroscience Center, Louisiana State University Medical Center School of Medicine, 2020 Gravier Street, Suite B, 70112, New Orieans, Louisiana

    Nicolas G. Bazan & Victor L. Marcheselli

  5. Institut Henri Beaufour, Le Plessis Robinson, France

    Pierre Braquet

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Bazan, N.G., Squinto, S.P., Braquet, P. et al. Platelet-activating factor and polyunsaturated fatty acids in cerebral ischemia or convulsions: Intracellular PAF-binding sites and activation of a fos/jun/AP-1 transcriptional signaling system. Lipids 26, 1236–1242 (1991). https://doi.org/10.1007/BF02536539

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  • DOI: https://doi.org/10.1007/BF02536539

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