Ciguatoxins and brevetoxins, neurotoxic polyether compounds active on sodium channels

Ciguatoxins (CTXs) and brevetoxins (PbTxs) modify the activation and inactivation processes of voltage-sensitive sodium channels (VSSC). In this study, the specific binding to rat brain synaptosomes of two commercial PbTxs, five purified CTXs and their derivatives was evaluated in competition with various concentrations of radiolabelled brevetoxin ([3H]PbTx-3). The results indicate that all CTXs bind specifically and with high affinity to sodium channels. Statistical analysis of the calculated inhibition constants identified two classes of toxins: the PbTxs and the less polar CTXs, and a group of CTXs of very high affinity. Relatively small chemical differences between 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 neuroblastoma cells, and their acute toxicity was determined in mice. CTXs have shown high affinities to VSSC of rat brain membranes and strong cytotoxic effects on neuroblastoma cells which correlate with their very low LD50 in mice. For PbTxs, it is different. Although binding with high affinity to VSSC and giving rise to significant cytotoxic effects, they are known to be poorly toxic intraperitoneally to mice. Furthermore, within the CTXs family, even though the most toxic compound (CTX-1B) has the highest affinity and the less toxic one (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-dependent cytotoxicity on neuroblastoma cells. These data suggest that the high toxicity of CTXs is related to sodium-dependent disturbances of the excitable membranes but might also involve other cellular mechanisms.