Prolonged exposure to WIN55,212-2 causes downregulation of the CB1 receptor and the development of tolerance to its anticonvulsant effects in the hippocampal neuronal culture model of acquired epilepsy.
Prolonged exposure to WIN55,212-2 causes downregulation of the CB1 receptor and the development of tolerance to its anticonvulsant effects in the hippocampal neuronal culture model of acquired epilepsy.
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DOI：
10.1016/j.neuropharm.2009.06.007
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发表时间：
2009-09
影响因子：
4.7
通讯作者：
DeLorenzo, Robert J.
中科院分区：
文献类型：
--
作者：
Blair, Robert E.;Deshpande, Laxmikant S.;Sombati, Sompong;Elphick, Maurice R.;Martin, Billy R.;DeLorenzo, Robert J.
大麻素在癫痫持续状态（SE）和获得性癫痫（AE）的体内和体外模型中均显示出CB 1受体依赖性抗惊厥活性。在这些模型中已经进一步证明，内源性大麻素系统以紧张的方式通过CB 1受体依赖性途径抑制癫痫发作放电。虽然急性大麻素治疗具有抗惊厥活性，但关于长期暴露于CB 1激动剂和耐受性发展对癫痫表型的影响知之甚少。本研究旨在评估长期暴露于CB 1激动剂WIN 55，212-2对海马神经元培养模型中低Mg 2+诱导的自发复发性癫痫样放电（SRED）的癫痫发作活动的影响。在低Mg 2+诱导的SRED后，将培养物返回至含有10、100或1000 nM WIN 55，212-2的维持培养基中4至24小时。WIN 55，212-2处理的培养物的全细胞电流钳分析揭示了SRED频率的浓度依赖性增加。免疫细胞化学染色显示，WIN 55，212-2处理诱导的CB 1受体的神经元过程中，并在多巴胺能和GABA能突触前末梢的浓度依赖性下调。在低Mg 2+处理的培养物中，长期暴露于无活性对映体WIN 55，212-3对SRED或CB 1受体染色的频率没有影响。本研究的结果进一步证实了强直性CB 1受体依赖性内源性大麻素对癫痫发作放电的调节作用，并表明长期暴露于大麻素导致对大麻素抗惊厥作用的耐受性的发展和癫痫表型中癫痫发作活动的加剧。
Cannabinoids have been shown to cause CB1-receptor dependent anticonvulsant activity in both in vivo and in vitro models of status epilepticus (SE) and acquired epilepsy (AE). It has been further demonstrated in these models that the endocannabinoid system functions in a tonic manner to suppress seizure discharges through a CB1-receptor dependent pathway. Although acute cannabinoid treatment has anticonvulsant activity, little is known concerning the effects of prolonged exposure to CB1 agonists and development of tolerance on the epileptic phenotype. This study was carried out to evaluate the effects of prolonged exposure to the CB1 agonist WIN55,212-2 on seizure activity in a hippocampal neuronal culture model of low-Mg2+ induced spontaneous recurrent epileptiform discharges (SREDs). Following low-Mg2+ induced SREDs, cultures were returned to maintenance media containing 10, 100 or 1000 nM WIN55,212-2 from 4 to 24 hours. Whole-cell current-clamp analysis of WIN55,212-2 treated cultures revealed a concentration-dependent increase in SRED frequency. Immunocytochemical staining revealed that WIN55,212-2 treatment induced a concentration-dependent down-regulation of the CB1 receptor in neuronal processes and at both glutamatergic and GABAergic presynaptic terminals. Prolonged exposure to the inactive enantiomer WIN55,212-3 in low-Mg2+ treated cultures had no effect on the frequency of SREDs or CB1 receptor staining. The results from this study further substantiate a role for a tonic CB1 receptor-dependent endocannabinoid regulation of seizure discharge and suggest that prolonged exposure to cannabinoids results in the development of tolerance to the anticonvulsant effects of cannabinoids and an exacerbation of seizure activity in the epileptic phenotype.
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DOI：
10.1073/pnas.93.18.9844
发表时间：
1996-09-03
影响因子：
11.1
作者：
Cao, YX;Wilcox, KS;Dichter, MA
通讯作者：
Dichter, MA
影响因子：
2.9
作者：
KARLER, R;TURKANIS, SA
通讯作者：
TURKANIS, SA
影响因子：
4.7
作者：
Hsieh, C;Brown, S;Mackie, K
通讯作者：
Mackie, K
影响因子：
3.6
作者：
González, S;Cebeira, M;Fernández-Ruiz, J
通讯作者：
Fernández-Ruiz, J
影响因子：
5
作者：
Breivogel, CS;Scates, SM;Martin, BR
通讯作者：
Martin, BR