RT Journal Article
T1 Effect of Gambierol and Its Tetracyclic and Heptacyclic Analogues in Cultured Cerebellar Neurons: A Structure−Activity Relationships Study
A1 Pérez, Sheila
A1 Vale González, María del Carmen
A1 Alonso, Eva
A1 Fuwa, Haruhiko
A1 Sasaki, Makoto
A1 Konno, Yu
A1 Goto, Tomomi
A1 Suga, Yuto
A1 Rodríguez Vieytes, Mercedes
A1 Botana López, Luis Miguel
K1 Gambierol
K1 Voltage-gated K+ channels
K1 Voltage-gated Na+ channel
K1 Calcium oscillations
K1 Cytotoxicity
K1 Cerebellar granule cell
AB 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.
PB American Chemical Society
YR 2012
FD 2012-08-15
LK https://hdl.handle.net/10347/47310
UL https://hdl.handle.net/10347/47310
LA eng
NO Pérez S, Vale C, Alonso E, Fuwa H, Sasaki M, Konno Y, Goto T, Suga Y, Vieytes MR, Botana LM. Effect of gambierol and its tetracyclic and heptacyclic analogues in cultured cerebellar neurons: a structure-activity relationships study. Chem Res Toxicol. 2012 Sep 17;25(9):1929-37. doi: 10.1021/tx300242m. Epub 2012 Aug 29. PMID: 22894724.
NO This document is the Accepted Manuscript version of a Published Article that appeared in final form in Chemical Research in Toxicology, copyright © 2012 American Chemical Society. To access the final published article, see https://doi.org/10.1021/tx300242m
NO This work was funded with the following FEDER cofunded-grants: From Ministerio de Ciencia y Tecnología, Spain: SAF2009-12581 (subprograma NEF), AGL2009-13581-CO2-01, TRA2009-0189, AGL2010-17875. From Xunta de Galicia, Spain: GRC 2010/10, and PGDIT 07MMA006261PR, PGIDIT (INCITE) 09MMA003261PR, PGDIT (INCITE) 09261080PR, 2009/XA044, and 10PXIB261254 PR. From EU VIIth Frame Program: 211326 - CP (CONffIDENCE), 265896 BAMMBO, 265409 µAQUA, and 262649 BEADS, 312184 PharmaSea. From the Atlantic Area Programme (Interreg IVB Transnational): 2009-1/117 Pharmatlantic. From the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan: Grants-in-Aid for Scientific Research on Innovative Areas (Nos. 24102507 and 23102016). From the Japan Society for Promotion of Science (JSPS): Grant-in-Aid for Young Scientists (A) (No. 23681045) and Grant-in-Aid for Scientific Research (A) (No. 21241050).
DS Minerva
RD 22 may 2026