Platelet activating factor-induced neuronal apoptosis is initiated independently of its G-protein coupled PAF receptor and is inhibited by the benzoate orsellinic acid.

Tue, 10/20/2015 - 10:21 -- Tracy Wysote
TitlePlatelet activating factor-induced neuronal apoptosis is initiated independently of its G-protein coupled PAF receptor and is inhibited by the benzoate orsellinic acid.
Publication TypeResearch
Year of Publication2007
AuthorsRyan SD, Harris CS, Mo F, Lee H, Hou ST, Bazan NG, Haddad PS, Arnason JT, Bennett SAL
KeywordsAnimals, Anti Diabetic Plant Project, Apoptosis, Benzoates, Caspase Inhibitors, Cells, Cultured, Crosses, Genetic, Enzyme Inhibitors, Gene Transfer Techniques, Mice, Mice, Knockout, Neurons, Platelet Activating Factor, Platelet Membrane Glycoproteins, Receptors, G-Protein-Coupled, Resorcinols, Signal Transduction
Abstract

The bioactive lipid mediator platelet activating factor (PAF) is recognized as a key effecter of neuronal apoptosis, yet it is not clear whether its G-protein coupled receptor (PAFR) initiates or prevents PAF neurotoxicity. Using PAFR-/- and congenic wild-type mice, we show that PAF triggers caspase-3/7 activity and neuronal death in PAFR-/- but not PAFR+/+ cerebellar granule neurons. Restoring receptor expression by recombinant adenoviral infection protected cells from PAF challenge. Neuronal death was not mediated by nitric oxide or N-methyl-d-aspartate receptor signaling given that N-nitro-l-arginine methyl ester and MK-801 did not inhibit PAF-induced neuronal loss in PAFR-/- neurons. To intervene in PAFR-independent neurotoxicity, the anti-apoptotic actions of three structurally distinct PAF antagonists were compared to a panel of plant and fungal benzoic acid derivatives. We found that the PAF antagonist BN 52021 but not FR 49175 or CV 3988 inhibited PAFR-independent neurotoxicity. Orsellinic acid, a fungal-derived benzoic acid, blocked PAF-mediated neuronal apoptosis without affecting PAFR-mediated neuroprotection. These findings demonstrate that PAF can transduce apoptotic death in primary neurons independently of its G-protein coupled receptor, that PAFR activation is neuroprotective, and that orsellinic acid effectively attenuates PAFR-independent neuronal apoptosis.

DOI10.1111/j.1471-4159.2007.04740.x
PubMed ID17877634
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