School of Pharmacy, University of Reading, Whiteknights, Reading RG6 6AJ, UK.
J Pharmacol Exp Ther. 2010 Feb;332(2):569-77. doi: 10.1124/jpet.109.159145. Epub 2009 Nov 11.
Plant-derived cannabinoids (phytocannabinoids) are compounds with emerging therapeutic potential. Early studies suggested that cannabidiol (CBD) has anticonvulsant properties in animal models and reduced seizure frequency in limited human trials. Here, we examine the antiepileptiform and antiseizure potential of CBD using in vitro electrophysiology and an in vivo animal seizure model, respectively. CBD (0.01-100 muM) effects were assessed in vitro using the Mg(2+)-free and 4-aminopyridine (4-AP) models of epileptiform activity in hippocampal brain slices via multielectrode array recordings. In the Mg(2+)-free model, CBD decreased epileptiform local field potential (LFP) burst amplitude [in CA1 and dentate gyrus (DG) regions] and burst duration (in all regions) and increased burst frequency (in all regions). In the 4-AP model, CBD decreased LFP burst amplitude (in CA1 only at 100 muM CBD), burst duration (in CA3 and DG), and burst frequency (in all regions). CBD (1, 10, and 100 mg/kg) effects were also examined in vivo using the pentylenetetrazole model of generalized seizures. CBD (100 mg/kg) exerted clear anticonvulsant effects with significant decreases in incidence of severe seizures and mortality compared with vehicle-treated animals. Finally, CBD acted with only low affinity at cannabinoid CB(1) receptors and displayed no agonist activity in [(35)S]guanosine 5'-O-(3-thio)triphosphate assays in cortical membranes. These findings suggest that CBD acts, potentially in a CB(1) receptor-independent manner, to inhibit epileptiform activity in vitro and seizure severity in vivo. Thus, we demonstrate the potential of CBD as a novel antiepileptic drug in the unmet clinical need associated with generalized seizures.
植物源性大麻素（植物大麻素）是具有新兴治疗潜力的化合物。早期研究表明，大麻二酚（CBD）在动物模型中具有抗惊厥特性，并在有限的人体试验中降低了癫痫发作频率。在这里，我们分别使用体外电生理学和体内动物癫痫模型来研究 CBD 的抗惊厥和抗癫痫作用。通过多电极阵列记录，在海马脑片的 Mg(2+)-free 和 4-aminopyridine (4-AP) 癫痫样活动模型中，评估了 CBD（0.01-100 μM）的体外作用。在 Mg(2+)-free 模型中，CBD 降低了癫痫样局部场电位（LFP）爆发幅度[在 CA1 和齿状回（DG）区域]和爆发持续时间（在所有区域），并增加了爆发频率（在所有区域）。在 4-AP 模型中，CBD 降低了 LFP 爆发幅度（仅在 CA1 区域，100 μM CBD）、爆发持续时间（在 CA3 和 DG）和爆发频率（在所有区域）。还通过戊四氮模型的全身性癫痫发作，在体内研究了 CBD（1、10 和 100 mg/kg）的作用。与 vehicle 处理的动物相比，CBD（100 mg/kg）明显降低了严重癫痫发作的发生率和死亡率，表现出明显的抗惊厥作用。最后，CBD 在皮质膜中的 [(35)S]guanosine 5'-O-(3-thio)triphosphate 测定中仅以低亲和力作用于大麻素 CB(1)受体，并且没有激动剂活性。这些发现表明，CBD 在体外抑制癫痫样活动和体内癫痫发作严重程度的作用可能是通过 CB(1)受体非依赖性方式发挥的。因此，我们证明了 CBD 在与全身性癫痫发作相关的未满足的临床需求中作为一种新型抗癫痫药物的潜力。
