McElroy Dan L, Roebuck Andrew J, Greba Quentin, Garai Sumanta, Brandt Asher L, Yilmaz Orhan, Cain Stuart M, Snutch Terrance P, Thakur Ganesh A, Laprairie Robert B, Howland John G
Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.
School of Liberal Arts, Yukon University, Whitehorse, YT Y1A 5K4, Canada.
IBRO Neurosci Rep. 2022 Jan 24;12:121-130. doi: 10.1016/j.ibneur.2022.01.006. eCollection 2022 Jun.
Childhood absence epilepsy (CAE) is a non-convulsive seizure disorder primarily in children characterized by absence seizures. Absence seizures consist of 2.5-5 Hz spike-and-wave discharges (SWDs) detectable using electroencephalography (EEG). Current drug treatments are only partially effective and adverse side effects have spurred research into alternative treatment approaches. Recent research shows that positive allosteric modulation of the type-1 cannabinoid receptor (CB1R) reduces the frequency and duration of SWDs in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a model that recapitulates the SWDs in CAE. Here, we tested additional CB1R ago-PAMs, GAT591 and GAT593, for their potential in alleviating SWD activity in GAERS. experiments confirm that GAT591 and GAT593 exhibit increased potency and selectivity in cell cultures and behave as CB1R allosteric agonists and PAMs. To assess drug effects on SWDs, bilateral electrodes were surgically implanted in the somatosensory cortices of male GAERS and EEGs recorded for 4 h following systemic administration of GAT591 or GAT593 (1.0, 3.0 and 10.0 mg/kg). Both GAT591 and GAT593 dose-dependently reduced total SWD duration during the recording period. The greatest effect on SWD activity was observed at 10.0 mg/kg doses, with GAT591 and GAT593 reducing seizure duration by 36% and 34% respectively. Taken together, these results support the continued investigation of CB1R PAMs as a potential therapeutic to alleviate SWDs in absence epilepsy.
儿童失神癫痫（CAE）是一种主要发生在儿童身上的非惊厥性癫痫障碍，其特征为失神发作。失神发作由可通过脑电图（EEG）检测到的2.5 - 5赫兹棘慢波放电（SWD）组成。目前的药物治疗仅部分有效，且不良副作用促使人们对替代治疗方法展开研究。最近的研究表明，对1型大麻素受体（CB1R）进行正向变构调节可降低来自斯特拉斯堡的遗传性失神癫痫大鼠（GAERS）的SWD频率和持续时间，GAERS是一种模拟CAE中SWD的模型。在此，我们测试了另外两种CB1R前变构调节剂GAT591和GAT593在减轻GAERS中SWD活动方面的潜力。实验证实，GAT591和GAT593在细胞培养中表现出增强的效力和选择性，并且表现为CB1R变构激动剂和前变构调节剂。为了评估药物对SWD的影响，将双侧电极手术植入雄性GAERS的体感皮层，并在全身给予GAT591或GAT593（1.0、3.0和10.0毫克/千克）后记录4小时的脑电图。GAT591和GAT593均剂量依赖性地减少了记录期间的总SWD持续时间。在10.0毫克/千克剂量下观察到对SWD活动影响最大，GAT591和GAT593分别将癫痫发作持续时间减少了36%和34%。综上所述，这些结果支持继续研究CB1R前变构调节剂作为减轻失神癫痫中SWD的潜在治疗方法。
