The polycyclic
ether class of marine natural products has attracted the attention of researchers due to their complex and large chemical structures and diverse
biological activities.
Gambierol is a marine polycyclic
ether toxin, first isolated along with
ciguatoxin congeners from the dinoflagellate Gambierdiscus toxicus. The parent compound
gambierol and the analogues evaluated in this work share the main crucial elements for
biological activity, previously described to be the C28=C29 double bond within the H ring and the unsaturated side chain [Fuwa, H., Kainuma, N., Tachibana, K., Tsukano, C., Satake, M., and Sasaki, M. (2004) Diverted total synthesis and
biological evaluation of
gambierol analogues: Elucidation of crucial structural elements for potent toxicity. Chem. Eur. J. 10, 4894-4909]. With the aim to gain a deeper understanding of the cellular mechanisms involved in the
biological activity of these compounds, we compared its activity in primary cultured neurons. The three compounds inhibited
voltage-gated potassium channels (Kv) in a concentration-dependent manner and with similar potency, caused a small inhibition of
voltage-gated sodium channels (Nav), and evoked cytosolic calcium oscillations. Moreover, the three compounds elicited a "loss of function" effect on Kv channels at concentrations of 0.1 nM. Additionally, both the tetracyclic and the heptacyclic derivatives of
gambierol elicited synchronous calcium oscillations similar to those previously described for
gambierol in cultured cerebellar neurons. Neither
gambierol nor its tetracyclic derivative elicited cell toxicity, while the heptacyclic analogue caused a time-dependent decrease in cell viability. Neither the tetracyclic nor the heptacyclic analogues of
gambierol exhibited lethality in mice after ip injection of 50 or 80 μg/kg of each compound. Altogether, the results presented in this work support an identical mechanism of action for
gambierol and its tetracyclic and heptacyclic analogues and indicate a "loss of function" effect on
potassium channels even after administration of the three compounds at subnanomolar concentrations. In addition, because
gambierol is known to stabilize the closed state of Kv3 channels, the results presented in this paper may have implications for understanding of channel functions and for future development of
therapies against
ciguatera poisoning and
potassium channel-related diseases.