Lambert Initiative for Cannabinoid Therapeutics, The University of Sydney, Camperdown , Australia.
Discipline of Pharmacology, School of Pharmacy, Faculty of Medicine and Health, The University of Sydney, Camperdown, Australia.
Cannabis Cannabinoid Res. 2023 Jun;8(3):495-504. doi: 10.1089/can.2022.0145. Epub 2022 Oct 21.
The endocannabinoid system contributes to the homeostatic response to seizure activity in epilepsy, a disease of brain hyperexcitability. Indeed, studies using conventional epilepsy models have shown that seizures increase endocannabinoids in the brain. However, it is unknown whether endocannabinoids and structurally related fatty acid amides and monoacylglycerols are similarly released in response to acute seizures in animal models of drug-resistant epilepsy. Therefore, in this study, we investigated whether a hyperthermia-induced seizure increased concentrations of endocannabinoids and related signaling lipids in the mouse model of Dravet syndrome. We compared hippocampal concentrations of the major endocannabinoids and related monoglycerols and N-acylethanolamines in wild-type mice, naïve mice, and mice primed with a single, hyperthermia-induced, generalized tonic-clonic seizure. Samples were collected 5 and 60 min following the seizure and then analyzed with LC-MS/MS. We found that a hyperthermia-induced seizure in mice did not affect hippocampal concentrations of the major endocannabinoids, 2-AG and anandamide, or the N-acylethanolamines studied, although the sampling of tissue 5 min postseizure may have been too late to capture any effect on these lipids. Heterozygous deletion of alone did not affect these lipid signaling molecules. Notably, however, we found that a hyperthermia-induced seizure significantly increased hippocampal concentrations of the monoacylglycerols, 2-linoleoyl glycerol (2-LG) and 1-linoleoyl glycerol (1-LG), in mice. Our results show the unprecedented elevation of the lesser-studied endocannabinoid-related monoacylglycerols, 2-LG and 1-LG, following a hyperthermia-induced seizure in a mouse model of Dravet syndrome. Future research is needed to comprehensively explore the function of these lipid signaling molecules during seizure activity and whether their actions can be exploited to develop new therapeutics.
内源性大麻素系统有助于癫痫（一种大脑过度兴奋的疾病）中癫痫活动的体内平衡反应。事实上，使用传统癫痫模型的研究表明，癫痫会增加大脑中的内源性大麻素。然而，尚不清楚内源性大麻素和结构上相关的脂肪酸酰胺和单酰基甘油是否会以类似的方式在耐药性癫痫动物模型中对急性癫痫发作作出反应。因此，在这项研究中，我们研究了高热诱导的癫痫发作是否会增加 Dravet 综合征小鼠模型中内源性大麻素和相关信号脂质的浓度。我们比较了野生型小鼠、未处理的小鼠和单次高热诱导的全身性强直-阵挛性癫痫发作后预激的小鼠的海马内主要内源性大麻素和相关单甘油酯和 N-酰基乙醇胺的浓度。在癫痫发作后 5 和 60 分钟采集样本，然后用 LC-MS/MS 进行分析。我们发现，高热诱导的癫痫发作不会影响 小鼠的海马内主要内源性大麻素 2-AG 和花生四烯酸酰胺或研究的 N-酰基乙醇胺的浓度，尽管在癫痫发作后 5 分钟采集组织样本可能为时已晚，无法观察到对这些脂质的任何影响。 单独的杂合缺失不会影响这些脂质信号分子。然而，值得注意的是，我们发现高热诱导的癫痫发作显著增加了 小鼠海马内单酰基甘油 2-亚麻酰甘油（2-LG）和 1-亚麻酰甘油（1-LG）的浓度。我们的研究结果显示，在 Dravet 综合征小鼠模型中，高热诱导的癫痫发作后，较少研究的内源性大麻素相关单酰基甘油 2-LG 和 1-LG 的浓度空前升高。需要进一步的研究来全面探索这些脂质信号分子在癫痫发作活动中的功能，以及它们的作用是否可以被利用来开发新的治疗方法。
