Effects of azaspiracid-1, a potent cytotoxic agent, on primary neuronal cultures. A structure-activity relationship study.
Azaspiracids (AZAs) are marine phycotoxins with an unknown mechanism of action, implicated in human intoxications. We investigated the effect of azaspiracid-1 (AZA-1) on the cytosolic calcium concentration ([Ca2+]c), intracellular pH (pHi), and neuron viability in neuronal cultures. AZA-1 increased [Ca2+]c and decreased neuronal viability. The effects of several fragments of the AZA-1 molecule (13 different chemical structures) were examined. The ent-ABCD-azaspiracid-1 (2) showed similar potency to AZA-1 (1) in increasing [Ca2+]c but higher cytotoxity than AZA-1. The chemical structures containing only the ABCD or the ABCDE ring domains (3-8) caused a [Ca2+]c increase but did not alter cell viability. The compounds containing only the FGHI ring domain of AZA-1 (9-14) did not modify the [Ca2+]c or the cell viability. Therefore, the effect of AZA-1 on [Ca2+]c depends on the presence of the ABCD or the ABCDE-ring structure, but the complete chemical structure is needed to produce neurotoxic effects.
Vale
Carmen
C
Departamento de Farmacología, USC, Lugo, Spain.
Nicolaou
K C
KC
Frederick
Michael O
MO
Gómez-Limia
Belén
B
Alfonso
Amparo
A
Vieytes
Mercedes R
MR
Botana
Luis M
LM
D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D003599:Cytoskeleton / Q000187:drug effects; D003600:Cytosol / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007424:Intracellular Fluid / Q000737:chemistry; D008387:Marine Toxins / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000095702:Polyether Toxins
D000199:Actins; D000970:Antineoplastic Agents; D002118:Calcium; D008387:Marine Toxins; D013141:Spiro Compounds; C406592:azaspiracid; D000095702:Polyether Toxins