Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela, Lugo, Spain.
Chem Res Toxicol. 2012 Sep 17;25(9):1929-37. doi: 10.1021/tx300242m. Epub 2012 Aug 29.
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.
聚醚类海洋天然产物因其复杂而庞大的化学结构和多样的生物活性而引起了研究人员的关注。 Gambierol 是一种海洋聚醚毒素，最初与共生藻 Gambierdiscus toxicus 中的雪卡毒素同系物一起从共生藻中分离出来。本文评估的母体化合物 Gambierol 及其类似物具有先前描述的生物活性的关键要素，即 H 环内的 C28=C29 双键和不饱和侧链 [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]。为了更深入地了解这些化合物生物活性涉及的细胞机制，我们比较了它们在原代培养神经元中的活性。这三种化合物以浓度依赖的方式抑制电压门控钾通道 (Kv)，且具有相似的效力，对电压门控钠通道 (Nav) 有轻微抑制作用，并引起细胞质钙振荡。此外，这三种化合物在 0.1 nM 的浓度下对 Kv 通道产生“功能丧失”效应。此外， Gambierol 的四环和七环衍生物均在小脑神经元培养中引起类似 Gambierol 先前描述的同步钙振荡。Gambierol 及其四环衍生物均不会引起细胞毒性，而七环类似物会导致细胞活力随时间下降。Gambierol 的七环类似物在腹腔注射 50 或 80 μg/kg 每种化合物后，在小鼠中均未表现出致死性。总的来说，本文中的结果支持 Gambierol 及其四环和七环类似物具有相同的作用机制，并表明即使在以亚纳摩尔浓度施用这三种化合物后，对钾通道也具有“功能丧失”效应。此外，由于 Gambierol 已知可稳定 Kv3 通道的关闭状态，本文的结果可能对理解通道功能以及未来开发针对雪卡中毒和钾通道相关疾病的治疗方法具有重要意义。
