Prolonged status epilepticus (SE) in humans causes high mortality and brain inflammation-associated neuronal injury and morbidity in survivors. Currently, the only effective treatment is to terminate the seizures swiftly to prevent brain damage. However, reliance on acute therapies alone would be imprudent due to the required short response time. Follow-on therapies that can be delivered well after the SE onset are in an urgent need. Cannabinoid receptor type 2 (CB2), a G protein-coupled receptor that can be expressed by activated brain microglia, has emerged as an appealing anti-inflammatory target for brain conditions. In the current study, we reported that the CB2 inverse agonism by our current lead compound SMM-189 largely prevented the rat primary microglia-mediated inflammation and showed moderate neuroprotection against N-methyl-D-aspartic acid (NMDA) receptor-mediated excitotoxicity in rat primary hippocampal cultures containing both neurons and glia. Using a classical mouse model of epilepsy, in which SE was induced by systemic administration of kainate (30 mg/kg, i.p.) and proceeded for 1 h, we demonstrated that SE downregulated the CB1 but slightly upregulated CB2 receptor in the hippocampus. Transient treatment with SMM-189 (6 mg/kg, i.p., b.i.d.) after the SE was interrupted by diazepam (10 mg/kg, i.p.) prevented the seizure-induced cytokine surge in the brain, neuronal death, and behavioral impairments 24 h after SE. Our results suggest that CB2 inverse agonism might provide an adjunctive anti-inflammatory therapy that can be delivered hours after SE onset, together with NMDA receptor blockers and first-line anti-convulsants, to reduce brain injury and functional deficits following prolonged seizures.

中文翻译：

---

2型大麻素受体的逆激动作用在癫痫持续状态后具有抗炎和神经保护作用。

人体中持续的癫痫持续状态（SE）会导致高死亡率以及幸存者的脑炎症相关神经元损伤和发病率。当前，唯一有效的治疗方法是迅速终止癫痫发作以防止脑损伤。但是，由于所需的响应时间短，因此仅依靠急性疗法是不明智的。迫切需要在SE发作后可以很好地提供后续治疗。大麻素2型受体（CB2）是一种G蛋白偶联受体，可以通过活化的脑小胶质细胞表达，已成为针对脑部疾病的有吸引力的抗炎靶标。在目前的研究中 我们报道了我们目前的先导化合物SMM-189对CB2的反向激动作用在很大程度上预防了大鼠原发性小胶质细胞介导的炎症，并在N-甲基-D-天冬氨酸（NMDA）受体介导的兴奋性中毒性神经保护作用中神经元和神经胶质细胞。使用癫痫病的经典小鼠模型，其中SE是通过海藻酸盐（30 mg / kg，ip）的全身性给药诱导的，并进行了1 h，我们证明了SE下调了海马中的CB1但略微上调了CB2受体。SE被地西epa（10 mg / kg，ip）中断后，用SMM-189（6 mg / kg，ip，bid）进行的短暂治疗可预防癫痫发作诱发的脑细胞因子激增，神经元死亡和行为障碍24 h SE之后。