Acyl‐based anandamide uptake inhibitors cause rapid toxicity to C6 glioma cells at pharmacologically relevant concentrations

摘要: Compounds blocking the uptake of endogenous cannabinoid anandamide (AEA) have been used to explore functions system in CNS both vivo and vitro. In this study, effects four commonly acyl-based inhibitors [N-(4-hydroxyphenyl)arachidonylamide (AM404), N-(4-hydroxy-2-methylphenyl) arachidonoyl amide (VDM11), (5Z,8Z,11Z,14Z)-N-(3-furanylmethyl)-5,8,11,14-eicosatetraenamide (UCM707) (9Z)-N-[1-((R)-4-hydroxybenzyl)-2-hydroxyethyl]-9-octadecen-amide (OMDM2)] related compound arvanil on C6 glioma cell viability were investigated. All five compounds reduced ability cells accumulate calcein, total nucleic acid content increased activity lactate dehydrogenase recovered medium. AM404 (10 microm) VDM11 acted rapidly, reducing after 3 h exposure when densities 5,000 per well used. contrast, UCM707 (30 microm), OMDM2 produced a more slowly developing effect viability, although robust seen 6-9 exposure. At higher densities, toxicities reduced. Comparison with arachidonic acid, methyl ester, AEA, glycine oleic suggested that toxicity arachidonoyl-based was primarily acyl side-chain rather than head group. A variety pre-treatments possible metabolic pathways receptor targets tested, but only consistent protective treatment against these antioxidant N-acetyl-L-cysteine. It is concluded AM404, VDM11, produce rapid loss over same concentration range as required for inhibition AEA vitro, albeit longer latency. Such should be kept mind acyl-derived are probe function endocannabinoid CNS, particularly chronic administration protocols.