Garlet Quelen Iane, Pires Luana da Costa, Milanesi Laura Hautrive, Marafiga Joseane Righes, Baldisserotto Bernardo, Mello Carlos Fernando, Heinzmann Berta Maria
Post-Graduation Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
Post-Graduation Program in Pharmacology, Federal University of Santa Maria, Santa Maria, RS, Brazil.
Toxicol Appl Pharmacol. 2017 Oct 1;332:52-63. doi: 10.1016/j.taap.2017.07.010. Epub 2017 Jul 18.
(+)-Dehydrofukinone (DHF), isolated from Nectandra grandiflora (Lauraceae) essential oil, induces sedation and anesthesia by modulation of GABAa receptors. However, no study has addressed whether DHF modulates other cellular events involved in the control of cellular excitability, such as seizure behavior. Therefore, the aim of the present study was to investigate the effect of DHF on cellular excitability and seizure behavior in mice. For this purpose, we used isolated nerve terminals (synaptosomes) to examine the effect of DHF on the plasma membrane potential, the involvement of GABAa receptors and the downstream activation of Ca mobilization. Finally, we performed an in vivo assay in order to verify whether DHF could impact on seizures induced by pentylenetetrazole (PTZ) in mice. The results showed that DHF induced a GABA-dependent sustained hyperpolarization, sensitive to flumazenil and absent in low-[Cl] medium. Additionally, (1-100μM) DHF decreased KCl-evoked calcium mobilization over time in a concentration-dependent manner and this effect was prevented by flumazenil. DHF increased the latency to myoclonic jerks (10mg/kg), delayed the onset of generalized tonic-clonic seizures (10, 30 and 100mg/kg), and these effects were also blocked by the pretreatment with flumazenil. Our data indicate that DHF has anticonvulsant properties and the molecular target underlying this effect is likely to be the facilitation of GABAergic neuronal inhibition. The present study highlights the therapeutic potential of the natural compound DHF as a suppressor of neuronal excitability.
从大花楠（樟科）精油中分离得到的（+）-脱氢福库酮（DHF）通过调节GABAa受体诱导镇静和麻醉作用。然而，尚无研究探讨DHF是否会调节参与细胞兴奋性控制的其他细胞事件，如癫痫发作行为。因此，本研究的目的是研究DHF对小鼠细胞兴奋性和癫痫发作行为的影响。为此，我们使用分离的神经末梢（突触体）来检测DHF对质膜电位的影响、GABAa受体的参与情况以及钙动员的下游激活。最后，我们进行了一项体内试验，以验证DHF是否会影响小鼠戊四氮（PTZ）诱导的癫痫发作。结果表明，DHF诱导了一种对氟马西尼敏感的GABA依赖性持续超极化，且在低[Cl]培养基中不存在。此外，（1-100μM）DHF随时间以浓度依赖性方式降低了KCl诱导的钙动员，且这种作用被氟马西尼所阻断。DHF增加了肌阵挛抽搐的潜伏期（10mg/kg），延迟了全身强直阵挛性癫痫发作的起始（10、30和100mg/kg），并且这些作用也被氟马西尼预处理所阻断。我们的数据表明，DHF具有抗惊厥特性，这种作用的分子靶点可能是促进GABA能神经元抑制。本研究突出了天然化合物DHF作为神经元兴奋性抑制剂的治疗潜力。
