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

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TypeArticle
Journal titleJ.Neurochem.
Volume103
Issue1
Pages8897; # of pages: 10
SubjectACID; Animals; antagonists & inhibitors; Apoptosis; Benzoates; Biochemistry; Canada; Caspases; cell; CELLS; Cells,Cultured; Crosses,Genetic; cytology; drug effects; ENZYME; Enzyme Inhibitors; EXPRESSION; Gene Transfer Techniques; genetics; Glycoproteins; immunology; INFECTION; Laboratories; lipid; membrane; Membrane Glycoproteins; metabolism; METHYL; Mice; Mice,Knockout; Microbiology; Neurons; pharmacology; physiology; Platelet Activating Factor; Platelet Membrane Glycoproteins; receptor; Receptors,G-Protein-Coupled; Resorcinols; Signal Transduction; SYSTEM; SYSTEMS; toxicity
AbstractThe 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
Publication date
LanguageEnglish
AffiliationNRC Institute for Biological Sciences; National Research Council Canada
Peer reviewedNo
NRC numberRYAN2007
NPARC number9365422
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Record identifier739d67e4-f886-412c-a67e-ae994a7cd03e
Record created2009-07-10
Record modified2016-05-09
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