Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia.
Faculty of Medicine and Health, Discipline of Pharmacology, Sydney Pharmacy School, The University of Sydney, Sydney, NSW, Australia.
PLoS One. 2023 Jan 26;18(1):e0280842. doi: 10.1371/journal.pone.0280842. eCollection 2023.
A purified preparation of cannabidiol (CBD), a cannabis constituent, has been approved for the treatment of intractable childhood epilepsies such as Dravet syndrome. Extensive pharmacological characterization of CBD shows activity at numerous molecular targets but its anticonvulsant mechanism(s) of action is yet to be delineated. Many suggest that the anticonvulsant action of CBD is the result of G protein-coupled receptor 55 (GPR55) inhibition. Here we assessed whether Gpr55 contributes to the strain-dependent seizure phenotypes of the Scn1a+/- mouse model of Dravet syndrome. The Scn1a+/- mice on a 129S6/SvEvTac (129) genetic background have no overt phenotype, while those on a [129 x C57BL/6J] F1 background exhibit a severe phenotype that includes hyperthermia-induced seizures, spontaneous seizures and reduced survival. We observed greater Gpr55 transcript expression in the cortex and hippocampus of mice on the seizure-susceptible F1 background compared to those on the seizure-resistant 129 genetic background, suggesting that Gpr55 might be a genetic modifier of Scn1a+/- mice. We examined the effect of heterozygous genetic deletion of Gpr55 and pharmacological inhibition of GPR55 on the seizure phenotypes of F1.Scn1a+/- mice. Heterozygous Gpr55 deletion and inhibition of GPR55 with CID2921524 did not affect the temperature threshold of a thermally-induced seizure in F1.Scn1a+/- mice. Neither was there an effect of heterozygous Gpr55 deletion observed on spontaneous seizure frequency or survival of F1.Scn1a+/- mice. Our results suggest that GPR55 antagonism may not be a suitable anticonvulsant target for Dravet syndrome drug development programs, although future research is needed to provide more definitive conclusions.
一种大麻素大麻二酚（CBD）的纯化制剂已被批准用于治疗德拉维特综合征等难治性儿童癫痫。对 CBD 的广泛药理学特征研究表明，它在许多分子靶点上具有活性，但它的抗惊厥作用机制尚待阐明。许多人认为 CBD 的抗惊厥作用是 G 蛋白偶联受体 55（GPR55）抑制的结果。在这里，我们评估了 Gpr55 是否有助于德拉维特综合征 Scn1a+/- 小鼠模型的菌株依赖性惊厥表型。在 129S6/SvEvTac（129）遗传背景下的 Scn1a+/- 小鼠没有明显的表型，而在[129 x C57BL/6J] F1 背景下的 Scn1a+/- 小鼠则表现出严重的表型，包括发热诱导的惊厥、自发性惊厥和存活率降低。我们观察到，在易发生惊厥的 F1 背景下的小鼠的皮质和海马中 Gpr55 转录表达更高，而在不易发生惊厥的 129 遗传背景下的小鼠中则较低，这表明 Gpr55 可能是 Scn1a+/- 小鼠的遗传修饰因子。我们研究了 Gpr55 杂合基因缺失和 GPR55 抑制对 F1.Scn1a+/- 小鼠惊厥表型的影响。Gpr55 杂合基因缺失和用 CID2921524 抑制 GPR55 对 F1.Scn1a+/- 小鼠的热诱导性惊厥的温度阈值没有影响。在 F1.Scn1a+/- 小鼠的自发性惊厥频率或存活率方面，也没有观察到 Gpr55 杂合基因缺失的影响。我们的结果表明，尽管需要进一步研究以提供更明确的结论，但 GPR55 拮抗可能不是德拉维特综合征药物开发计划的合适抗惊厥靶点。
