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Platelet activating factor‐induced neuronal apoptosis is initiated independently of its G‐protein coupled PAF receptor and is inhibited by the benzoate orsellinic acid
Author(s) -
Ryan Scott D.,
Harris Cory S.,
Mo Fan,
Lee Haemi,
Hou Sheng T.,
Bazan Nicolas G.,
Haddad Pierre S.,
Arnason John T.,
Bennett Steffany A. L.
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04740.x
Subject(s) - neurotoxicity , neuroprotection , platelet activating factor , receptor , apoptosis , platelet activating factor receptor , biology , pharmacology , receptor antagonist , microbiology and biotechnology , chemistry , biochemistry , antagonist , immunology , toxicity , organic chemistry
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.