Ma Lei, Wang Li, Yang Feng, Meng Xian-Dong, Wu Chen, Ma Hui, Jiang Wen
Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
CNS Neurosci Ther. 2014 Oct;20(10):905-15. doi: 10.1111/cns.12302. Epub 2014 Jul 3.
Patients with temporal lobe epilepsy (TLE) often suffer from comorbid psychiatric diagnoses such as depression, anxiety, or impaired cognitive performance. Endocannabinoid (eCB) signaling is a key regulator of synaptic neurotransmission and has been implicated in the mechanisms of epilepsy as well as several mood disorders and cognitive impairments.
We employed a pilocarpine model of TLE in C57/BJ mice to investigate the role of eCB signaling in epileptogenesis and concomitant psychiatric comorbidities.
We sought to alter the neuronal levels of a known eCB receptor ligand, 2-arachidonylglycerol (2-AG), through the use of RHC80267 or JZL184. Pilocarpine-treated mice were treated with RHC80267 (1.3 μmol) or JZL184 (20 mg/kg) immediately after the termination of status epilepticus (SE), which was followed by daily treatment for the next 7 days. Our results indicated that RHC80267 treatment significantly reduced the percentage of mice suffering from spontaneous recurrent seizures (SRS) in addition to decreasing the duration of observed seizures when compared to vehicle treatment. Furthermore, RHC80267 attenuated depression and anxiety-related behaviors, improved previously impaired spatial learning and memory, and inhibited seizure-induced hippocampal neuronal loss during the chronic epileptic period. In contrast, JZL184 administration markedly increased the frequency and the duration of observed SRS, enhanced the previously impaired neuropsychological performance, and increased hippocampal damage following SE.
These findings suggest that RHC80267 treatment after the onset of SE could result in an amelioration of the effects found during the chronic epileptic period and yield an overall decrease in epileptic symptoms and comorbid conditions. Thus, alterations to endocannabinoid signaling may serve as a potential mechanism to prevent epileptogenesis and manipulation of this signaling pathway as a possible drug target.
颞叶癫痫（TLE）患者常伴有诸如抑郁、焦虑或认知功能受损等共病精神疾病诊断。内源性大麻素（eCB）信号是突触神经传递的关键调节因子，已被认为与癫痫机制以及多种情绪障碍和认知障碍有关。
我们在C57/BJ小鼠中采用毛果芸香碱诱导的TLE模型，以研究eCB信号在癫痫发生及伴发的共病精神疾病中的作用。
我们试图通过使用RHC80267或JZL184来改变一种已知的eCB受体配体2-花生四烯酸甘油（2-AG）的神经元水平。癫痫持续状态（SE）结束后，立即对毛果芸香碱处理的小鼠给予RHC80267（1.3 μmol）或JZL184（20 mg/kg），随后在接下来的7天进行每日治疗。我们的结果表明，与溶剂处理相比，RHC80267治疗显著降低了自发复发性癫痫发作（SRS）小鼠的百分比，同时缩短了观察到的癫痫发作持续时间。此外，RHC80267减轻了抑郁和焦虑相关行为，改善了先前受损的空间学习和记忆，并在慢性癫痫期抑制了癫痫发作诱导的海马神经元丢失。相比之下，给予JZL184显著增加了观察到的SRS的频率和持续时间，加重了先前受损的神经心理学表现，并增加了SE后海马的损伤。
这些发现表明，SE发作后给予RHC80267治疗可改善慢性癫痫期发现的影响，并总体上降低癫痫症状和共病情况。因此，内源性大麻素信号的改变可能是预防癫痫发生的潜在机制，并且操纵该信号通路可能成为一个潜在的药物靶点。
