Ciguatoxins and brevetoxins, neurotoxic polyether compounds active on sodium channels

Ciguatoxins (CTXs) and brevetoxins (PbTxs) modify the activation and inacti vation processes of voltage-sensitive sodium channels (VSSC). In this study , the specific binding to rat brain synaptosomes of two commercial PbTxs, f ive purified CTXs and their derivatives was evaluated in competition with v arious concentrations of radiolabelled brevetoxin ([H-3]PbTx-3). The result s indicate that all CTXs bind specifically and with high affinity to sodium channels. Statistical analysis of the calculated inhibition constants iden tified two classes of toxins: the PbTxs and the less polar CTXs, and a grou p of CTXs of very high affinity. Relatively small chemical differences betw een the CTXs gave rise to significant differences in their affinity to the rat brain sodium channels. Cytotoxic effects associated with sodium channel activation were evaluated for the two classes of toxins on murine neurobla stoma cells, and their acute toxicity was determined in mice. CTXs have sho wn high affinities to VSSC of rat brain membranes and strong cytotoxic effe cts on neuroblastoma cells which correlate with their very low LD50 in mice . For PbTxs, it is different. Although binding, own to be poorly toxic intr aperitonealy to mice. Furthermore, with high affinity to VSSC and giving ri se to significant cytotoxic effects, they are known to be poorly toxic intr aperitonealy to mice. Furthermore, within the CTXs family, even though the most toxic compound (CTX-1B) has the highest affinity and the less toxic on e (CTX-4B) the lowest affinity, a detailed analysis of the data pointed out a complex situation: (i) high affinity and toxicity seem to be related to the hydroxylation of the molecule on the A-ring rather than to the backbone type, (ii) acute toxicity in mice does not follow exactly the sodium-depen dent cytotoxicity on neuroblastoma cells. These data suggest that the high toxicity of CTXs is related to sodium-dependent disturbances of the excitab le membranes but might also involve other cellular mechanisms. (C) 1998 Els evier Science Ltd. an rights reserved.