Cannabidiol Modifies the Glutamate Over-Release in Brain Tissue of Patients and Rats with Epilepsy: A Pilot Study.
Cannabidiol Modifies the Glutamate Over-Release in Brain Tissue of Patients and Rats with Epilepsy: A Pilot Study.
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DOI：
10.3390/biomedicines11123237
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发表时间：
2023-12-07
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影响因子：
4.7
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中科院分区：
文献类型：
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耐药性癫痫（DRE）与细胞外高水平的谷氨酸有关。研究支持大麻二酚 (CBD) 减少谷氨酸过度释放的观点。这项研究的重点是调查 CBD 是否会减少从 DRE 患者以及癫痫临床前模型中获得的皮质突触末梢诱发的谷氨酸释放。突触末梢（突触体）取自接受癫痫手术的耐药颞叶癫痫（DR-TLE，n = 10）或耐药颞叶外癫痫（DR-ETLE，n = 10）患者的癫痫新皮质。通过 Percoll-蔗糖密度梯度高度纯化的突触体通过共聚焦显微镜和蛋白质印迹进行表征。突触体用于估计在不同浓度的 CBD 存在下，高 KCl (33 mM) 诱发的谷氨酸释放。我们的结果显示从 7 名 DR-TLE 患者和 7 名 DR-ETLE 患者获得的反应组织。当与低浓度（低于 100 µM）的 CBD 一起孵育时，反应组织显示出较低的谷氨酸释放（p < 0.05），但在较高浓度下则不然。尽管暴露于不同浓度的 CBD，但对 CBD 无反应的组织（DR-TLE，n = 3 和 DR-ELTE，n = 3）显示出高谷氨酸释放量。同时，使用人类癫痫新皮质块通过全细胞和细胞外电生理记录来确定其活力。电生理学评估支持本研究中使用的反应性和非反应性人类癫痫新皮质表现出适当的神经元活力和稳定性以获得电生理反应。我们还研究了 CBD 的亚慢性给药是否可以减少颞叶癫痫临床前模型中谷氨酸的过度释放。对锂-毛果芸香碱诱发自发性反复发作的大鼠施用 CBD（200 mg/kg，每 24 小时口服一次，持续 7 天）可减少海马中谷氨酸的过度释放。目前的研究表明，急性暴露于低浓度的 CBD 可以减少从一些 DRE 患者获得的突触末梢中谷氨酸的过度释放。当亚慢性应用于自发性复发性癫痫发作的大鼠时，这种效果也很明显。一个重要的发现是确定了一组对 CBD 效果无反应的患者。未来的研究对于确定对 CBD 反应的生物标志物以控制 DRE 至关重要。
Drug-resistant epilepsy (DRE) is associated with high extracellular levels of glutamate. Studies support the idea that cannabidiol (CBD) decreases glutamate over-release. This study focused on investigating whether CBD reduces the evoked glutamate release in cortical synaptic terminals obtained from patients with DRE as well as in a preclinical model of epilepsy. Synaptic terminals (synaptosomes) were obtained from the epileptic neocortex of patients with drug-resistant temporal lobe epilepsy (DR-TLE, n = 10) or drug-resistant extratemporal lobe epilepsy (DR-ETLE, n = 10) submitted to epilepsy surgery. Synaptosomes highly purified by Percoll-sucrose density gradient were characterized by confocal microscopy and Western blot. Synaptosomes were used to estimate the high KCl (33 mM)-evoked glutamate release in the presence of CBD at different concentrations. Our results revealed responsive tissue obtained from seven patients with DR-TLE and seven patients with DR-ETLE. Responsive tissue showed lower glutamate release (p < 0.05) when incubated with CBD at low concentrations (less than 100 µM) but not at higher concentrations. Tissue that was non-responsive to CBD (DR-TLE, n = 3 and DR-ELTE, n = 3) showed high glutamate release despite CBD exposure at different concentrations. Simultaneously, a block of the human epileptic neocortex was used to determine its viability through whole-cell and extracellular electrophysiological recordings. The electrophysiological evaluations supported that the responsive and non-responsive human epileptic neocortices used in the present study exhibited proper neuronal viability and stability to acquire electrophysiological responses. We also investigated whether the subchronic administration of CBD could reduce glutamate over-release in a preclinical model of temporal lobe epilepsy. Administration of CBD (200 mg/kg, p.o. every 24 h for 7 days) to rats with lithium-pilocarpine-evoked spontaneous recurrent seizures reduced glutamate over-release in the hippocampus. The present study revealed that acute exposure to low concentrations of CBD can reduce the glutamate over-release in synaptic terminals obtained from some patients with DRE. This effect is also evident when applied subchronically in rats with spontaneous recurrent seizures. An important finding was the identification of a group of patients that were non-responsive to CBD effects. Future studies are essential to identify biomarkers of responsiveness to CBD to control DRE.
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影响因子：
14
作者：
Chun C;Smith AST;Kim H;Kamenz DS;Lee JH;Lee JB;Mack DL;Bothwell M;Clelland CD;Kim DH
通讯作者：
Kim DH
影响因子：
3.4
作者：
Britch SC;Babalonis S;Walsh SL
通讯作者：
Walsh SL
影响因子：
3.4
作者：
Bouwman, Brigitte M.;Suffczynski, Piotr;van Rijn, Clementina M.
通讯作者：
van Rijn, Clementina M.
影响因子：
5.6
作者：
Crippa, Jose A. S.;Crippa, Ana C. S.;Zuardi, Antonio W.
通讯作者：
Zuardi, Antonio W.
影响因子：
5.3
作者：
Crabtree, Gregg W.;Sun, Ziyi;Gogos, Joseph A.
通讯作者：
Gogos, Joseph A.