The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy
The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy
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DOI：
10.1124/jpet.103.051920
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发表时间：
2003-10-01
影响因子：
3.5
通讯作者：
DeLorenzo, RJ
中科院分区：
文献类型：
--
作者：
Wallace, MJ;Blair, RE;DeLorenzo, RJ
多项证据表明大麻素化合物具有抗惊厥作用。然而，大麻素的抗惊厥潜力以及内源性大麻素系统在调节癫痫发作活动中的作用尚未在以自发性、反复发作为特征的癫痫体内模型中进行测试。在这里，使用大鼠癫痫模型，我们显示大麻提取物 Delta(9)-四氢大麻酚 (10 mg/kg) 以及大麻模拟物 4,5-二氢-2-甲基- 4(4-吗啉基甲基)-1-(1-萘基-羰基)-6H-吡咯并[ 3,2,1-i, j] quinolin-6-one [R(+) WIN55,212 (5 mg/kg)]，完全消除自发性癫痫发作。相反，应用大麻素 CB 1 受体 ( CB 1) 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)，显着增加癫痫发作持续时间和频率。在一些动物中，CB1 受体拮抗剂导致癫痫发作持续时间延长此外，我们确定在短期毛果芸香碱诱导的癫痫发作期间，海马脑区域内源性 CB1 配体 2-花生四烯酰甘油的水平显着增加。这些数据不仅表明外源性大麻素具有抗惊厥活性，而且还表明内源性大麻素通过激活 CB1 受体来调节癫痫发作终止和持续时间。免疫组织化学分析表明，癫痫海马 CA 区域的 CB1 受体蛋白表达显着增加。通过证明内源性大麻素系统在调节癫痫活动中的作用，这些研究明确了内源性大麻素系统在调节神经兴奋中的作用，并表明 CB1 受体的可塑性与癫痫有关。
Several lines of evidence suggest that cannabinoid compounds are anticonvulsant. However, the anticonvulsant potential of cannabinoids and, moreover, the role of the endogenous cannabinoid system in regulating seizure activity has not been tested in an in vivo model of epilepsy that is characterized by spontaneous, recurrent seizures. Here, using the rat pilocarpine model of epilepsy, we show that the marijuana extract Delta(9)-tetrahydrocannabinol ( 10 mg/kg) as well as the cannabimimetic, 4,5-dihydro-2-methyl- 4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[ 3,2,1-i, j] quinolin-6-one [R(+) WIN55,212 (5 mg/kg)], completely abolished spontaneous epileptic seizures. Conversely, application of the cannabinoid CB 1 receptor ( CB 1) antagonist, N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl- 1H-pyrazole-3-carboxamidehydrochloride (SR141716A), significantly increased both seizure duration and frequency. In some animals, CB1 receptor antagonism resulted in seizure durations that were protracted to a level consistent with the clinical condition status epilepticus. Furthermore, we determined that during an short-term pilocarpine-induced seizure, levels of the endogenous CB1 ligand 2-arachidonylglycerol increased significantly within the hippocampal brain region. These data indicate not only anticonvulsant activity of exogenously applied cannabinoids but also suggest that endogenous cannabinoid tone modulates seizure termination and duration through activation of the CB1 receptor. Furthermore, Western blot and immunohistochemical analyses revealed that CB1 receptor protein expression was significantly increased throughout the CA regions of epileptic hippocampi. By demonstrating a role for the endogenous cannabinoid system in regulating seizure activity, these studies define a role for the endogenous cannabinoid system in modulating neuroexcitation and suggest that plasticity of the CB1 receptor occurs with epilepsy.