| Author | Search for: Ryan, S.; Search for: Harris, C.; Search for: Mo, F.; Search for: Lee, H.; Search for: Hou, S.; Search for: Bazan, N.; Search for: Haddad, P.; Search for: Arnason, J.; Search for: Bennett, S. |
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| Format | Text, Article |
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| Subject | acid; antagonists & inhibitors; apoptosis; benzoates; biochemistry; Canada; caspases; cell; 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; toxicity |
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| 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 |
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| Publication date | 2007-10 |
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| In | |
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| Language | English |
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| NRC number | RYAN2007 |
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| NPARC number | 9365422 |
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| Export citation | Export as RIS |
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| Report a correction | Report a correction (opens in a new tab) |
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| Record identifier | 739d67e4-f886-412c-a67e-ae994a7cd03e |
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| Record created | 2009-07-10 |
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| Record modified | 2020-05-10 |
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