期刊
CHEMICAL RESEARCH IN TOXICOLOGY
卷 25, 期 9, 页码 1929-1937出版社
AMER CHEMICAL SOC
DOI: 10.1021/tx300242m
关键词
-
资金
- Ministerio de Ciencia y Tecnologia, Spain [SAF2009-12581, AGL2009-13581-CO2-01, TRA2009-0189, AGL2010-17875]
- Xunta de Galicia, Spain [GRC 2010/10, PGDIT 07MMA006261PR, PGIDIT (INCITE) 09MMA003261PR, PGDIT (INCITE) 09261080PR, 2009/XA044, 10PXIB261254 PR]
- EU [211326-CP (CONffIDENCE), 265896 BAMMBO, 265409 muAQUA, 262649 BEADS, 312184 PharmaSea]
- Atlantic Area Programme (Interreg IVB Trans-national) [2009-1/117]
- Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan [24102507, 23102016]
- Japan Society for Promotion of Science (JSPS) [23681045, 21241050]
- FEDER
- Grants-in-Aid for Scientific Research [23681045, 21241050, 24102507, 23102016] Funding Source: KAKEN
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 (Nay), 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 mu g/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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据