Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity.
Evidence for a physiological role of endocannabinoids in the modulation of seizure threshold and severity.
复制标题
内源性大麻素在调节癫痫阈值和严重程度中的生理作用的证据。
DOI：
10.1016/s0014-2999(02)02331-2
复制
发表时间：
2002
影响因子：
5
通讯作者：
DeLorenzo,RobertJ
中科院分区：
文献类型：
--
作者：
Wallace,MelisaJ;Martin,BillyR;DeLorenzo,RobertJ
大麻素的抗惊厥作用已被证明是通过激活大麻素 CB1 受体介导的。本研究旨在评估内源性大麻素（内源性大麻素）对癫痫发作严重程度和阈值的影响。使用雄性 CF-1 小鼠在最大电击癫痫模型中评估了内源性大麻素花生四烯乙醇胺（anandamide）的抗惊厥作用，结果发现它是一种完全有效的抗惊厥药（ED50 = 50 mg/kg i.p.）。代谢稳定的 anandamide 类似物 (R)-(20-cyano-16,16-dimetyldocosa-cis-5,8,11,14-tetraenoyl)-1'-羟基-2'-丙胺 (O-1812) 也被确定为最大电击模型中的有效抗惊厥药（ED50 = 1.5 mg/kg i.p.）。此外，用大麻素CB1受体特异性拮抗剂N-(哌啶-1-基-5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-甲酰胺盐酸盐(SR141716A)预处理完全消除了anandamide以及O-1812的抗惊厥作用(P≤0.01，Fisher精确检验)，表明大麻素 CB1 受体介导的两种内源性大麻素化合物的抗惊厥机制此外，单独使用 SR141716A 评估了大麻素 CB1 受体内源性张力对最大癫痫阈值的影响，我们的数据表明，与媒介物治疗的动物相比，SR141716A（10 mg/kg i.p.）显着降低了最大癫痫阈值（CC50 = 14.27 mA）。 (CC50=17.57 mA)（效价比=1.23，置信下限=1.06，置信上限=1.43），表明存在调节癫痫活动的内源性大麻素音。这些数据表明 anandamide 及其类似物 O-1812 在整个动物模型中具有抗惊厥作用，并进一步表明大麻素 CB1 受体是癫痫调节的主要内源性位点。
The anticonvulsant effect of cannabinoids has been shown to be mediated through activation of the cannabinoid CB1receptor. This study was initiated to evaluate the effects of endogenously occurring cannabinoids (endocannabinoids) on seizure severity and threshold. The anticonvulsant effect of the endocannabinoid, arachidonylethanolamine (anandamide), was evaluated in the maximal electroshock seizure model using male CF-1 mice and was found to be a fully efficacious anticonvulsant (ED50=50 mg/kg i.p.). The metabolically stable analog of anandamide, (R)-(20-cyano-16,16-dimetyldocosa-cis-5,8,11,14-tetraenoyl)-1′-hydroxy-2′-propylamine (O-1812), was also determined to be a potent anticonvulsant in the maximal electroshock model (ED50=1.5 mg/kg i.p.). Furthermore, pretreatment with the cannabinoid CB1receptor specific antagonist N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A) completely abolished the anticonvulsant effect of anandamide as well as O-1812 (P≤0.01, Fisher exact test), indicating a cannabinoid CB1receptor-mediated anticonvulsant mechanism for both endocannabinoid compounds. Additionally, the influence of cannabinoid CB1receptor endogenous tone on maximal seizure threshold was assessed using SR141716A alone. Our data show that SR141716A (10 mg/kg i.p.) significantly reduced maximal seizure threshold (CC50=14.27 mA) compared to vehicle-treated animals (CC50=17.57 mA) (potency ratio=1.23, lower confidence limit=1.06, upper confidence limit=1.43), indicating the presence of an endogenous cannabinoid tone that modulates seizure activity. These data demonstrate that anandamide and its analog, O-1812, are anticonvulsant in a whole animal model and further implicate the cannabinoid CB1receptor as a major endogenous site of seizure modulation.