title: The Marine Guanidine Alkaloid Crambescidin 816 Induces Calcium Influx and Cytotoxicity in Primary Cultures of Cortical Neurons through Glutamate Receptors.
abstract: Crambescidin 816 is a guanidine alkaloid produced by the sponge Crambe crambe with known antitumoral activity. While the information describing the effects of this alkaloid in central neurons is scarce, Cramb816 is known to block voltage dependent calcium channels being selective for L-type channels. Moreover, Cramb816 reduced neuronal viability through an unknown mechanism. Here, we aimed to describe the toxic activity of Cramb816 in cortical neurons. Since calcium influx is considered the main mechanism responsible for neuronal cell death, the effects of Cramb816 in the cytosolic calcium concentration of cortical neurons were studied. The alkaloid decreased neuronal viability and induced a dose-dependent increase in cytosolic calcium that was also related to the presence of calcium in the extracellular media. The increase in calcium influx was age dependent, being higher in younger neurons. Moreover, this effect was prevented by glutamate receptor antagonists, which did not fully block the cytotoxic effect of Cramb816 after 24 h of treatment but completely prevented Cramb816 cytotoxicity after 10 min exposure. Therefore, the findings presented herein provide new insights into the cytotoxic effect of Cramb816 in cortical neurons.
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela , Lugo 27002, Spain.
authors.forename: Aida G
authors.initials: AG
authors.lastname: Mendez
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela , Lugo 27002, Spain.
authors.forename: Andrea Boente
authors.initials: AB
authors.lastname: Juncal
authors.affiliation: Geoazur, UMR Université Nice Sophia Antipolis-CNRS-IRD-OCA , 06560 Valbonne, France.|Laboratoire de Pharmacognosie, UMR CNRS 8076 BioCIS, LabEx LERMIT, Faculté de Pharmacie, Université Paris-Sud , 92290 Châtenay-Malabry, France.
authors.forename: Siguara B L
authors.initials: SBL
authors.lastname: Silva
authors.affiliation: Geoazur, UMR Université Nice Sophia Antipolis-CNRS-IRD-OCA , 06560 Valbonne, France.|School of Chemistry, Marine Biodiscovery, National University of Ireland Galway , Galway, Ireland.
authors.forename: Olivier P
authors.identifier: 0000-0002-5708-1409
authors.initials: OP
authors.lastname: Thomas
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela , Lugo 27002, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Martín Vázquez
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela , Lugo 27002, Spain.
authors.forename: Amparo
authors.initials: A
authors.lastname: Alfonso
authors.affiliation: Departamento de Fisiología, Facultad de Veterinaria, Universidad de Santiago de Compostela , Lugo 27002, Spain.
authors.forename: Mercedes R
authors.initials: MR
authors.lastname: Vieytes
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela , Lugo 27002, Spain.
authors.forename: Carmen
authors.identifier: 0000-0002-9842-6223
authors.initials: C
authors.lastname: Vale
authors.affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela , Lugo 27002, Spain.
authors.forename: Luís M
authors.initials: LM
authors.lastname: Botana
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002413:Cations, Divalent / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016922:Cellular Senescence; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D051379:Mice; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009543:Nifedipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D017470:Receptors, Glutamate / Q000378:metabolism*; D013141:Spiro Compounds / Q000737:chemistry / Q000633:toxicity*
chemical_list: D000470:Alkaloids; D002121:Calcium Channel Blockers; D002413:Cations, Divalent; D018691:Excitatory Amino Acid Antagonists; D017470:Receptors, Glutamate; D013141:Spiro Compounds; C083155:crambescidin 816; D009543:Nifedipine; D002118:Calcium
keywords: Guanidine alkaloids; cortical neurons; crambescidin 816; cytosolic Ca2+; cytotoxicity; glutamate receptors