| Auteur | Rechercher : Ryan, S.; Rechercher : Harris, C.; Rechercher : Mo, F.; Rechercher : Lee, H.; Rechercher : Hou, S.; Rechercher : Bazan, N.; Rechercher : Haddad, P.; Rechercher : Arnason, J.; Rechercher : Bennett, S. |
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| Format | Texte, Article |
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| Sujet | 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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| Résumé | 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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| Date de publication | 2007-10 |
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| Dans | |
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| Langue | anglais |
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| Numéro du CNRC | RYAN2007 |
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| Numéro NPARC | 9365422 |
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| Exporter la notice | Exporter en format RIS |
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| Signaler une correction | Signaler une correction (s'ouvre dans un nouvel onglet) |
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| Identificateur de l’enregistrement | 739d67e4-f886-412c-a67e-ae994a7cd03e |
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| Enregistrement créé | 2009-07-10 |
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| Enregistrement modifié | 2020-05-10 |
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