Platelet activating factor-induced neuronal apoptosis is initiated independently of its G-protein coupled PAF receptor and is inhibited by the benzoate orsellinic acid.
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.
Ryan
Scott D
SD
Department of Biochemistry, Microbiology, and Immunology, Neural Regeneration Laboratory and Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada.
Harris
Cory S
CS
Mo
Fan
F
Lee
Haemi
H
Hou
Sheng T
ST
Bazan
Nicolas G
NG
Haddad
Pierre S
PS
Arnason
John T
JT
Bennett
Steffany A L
SA
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001565:Benzoates / Q000494:pharmacology; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D003433:Crosses, Genetic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018014:Gene Transfer Techniques; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000633:toxicity*; D010980:Platelet Membrane Glycoproteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D001565:Benzoates; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; D012118:Resorcinols; C039351:platelet activating factor receptor; C501612:orsellinic acid