Antiepileptic effects of two Rho-kinase inhibitors, Y-27632 and fasudil, in mice
Antiepileptic effects of two Rho-kinase inhibitors, Y-27632 and fasudil, in mice
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DOI：
10.1038/bjp.2008.225
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发表时间：
2008-09-01
影响因子：
7.3
通讯作者：
Bueyuekafsar, K.
中科院分区：
文献类型：
--
作者：
Inan, S. Y.;Bueyuekafsar, K.
背景和目的：Rho/Rho激酶信号转导参与许多细胞事件，包括CNS中的一些事件。然而，这一途径在癫痫中的作用尚未得到评估。因此，我们确定了两种Rho激酶抑制剂Y-27632和法舒地尔对戊四唑（PTZ）或最大电休克（MES）诱导的癫痫发作的影响。Y-27632的作用（5-10 mg kg（-1））和法舒地尔（5-25 mg kg（-1））对肌阵挛性抽搐、阵挛性和强直性惊厥、强直性后肢伸展持续时间和强直性惊厥指数百分比的影响，用PTZ（65 mg·kg ~（-1））或MES（50 Hz，50 mA，0.4s）刺激小鼠，观察小鼠翻正反射的恢复潜伏期。这些抑制剂也在PTZ诱导的点燃模型上进行了测试（35 mg/kg，持续11天）。RhoA蛋白质的膜和胞浆水平测定从点燃mice.Key results：Y-27632和法舒地尔减少发病的小鼠给予PTZ的肌阵挛性抽搐，阵挛性惊厥和强直性后肢伸展。这些抑制剂可抑制MES兴奋小鼠的强直性惊厥指数和翻正反射恢复潜伏期。Western blotting结果表明，PTZ点燃小鼠脑匀浆中Rho向质膜的转位增加。然而，Rho-激酶抑制剂在给定的剂量没有改变运动coordinationsofthemice.Conclusions和影响：Rho/Rho-激酶信号转导可能发挥作用，在癫痫诱导的PTZ和MES。此外，Rho激酶抑制剂可能是新的重要的抗癫痫药物。
Background and purpose: Rho/Rho-kinase signalling is involved in many cellular events, including some in the CNS. However, the role of this pathway in epilepsy has not yet been assessed. Therefore, we determined the effects of two Rho-kinase inhibitors, Y-27632 and fasudil, on seizures induced by pentylenetetrazole (PTZ) or maximal electroconvulsive shock (MES).Experimental approach: Effects of Y-27632 (5-10 mg kg(-1)) and fasudil (5-25 mg kg(-1)) on duration of myoclonic jerks, clonic and tonic convulsions, tonic hindlimb extensions and percentage of tonic convulsion index, as well as recovery latency for righting reflex were investigated in mice stimulated with PTZ (65 mg kg(-1)) or MES (50 Hz, 50 mA and 0.4 s). These inhibitors were also tested on a model of kindling induced by PTZ (35 mg kg(-1), for 11 days). Membrane and cytosolic levels of RhoA protein were measured in brain homogenates from kindled mice.Key results: Y-27632 and fasudil diminished onset of myoclonic jerks, clonic convulsions and tonic hindlimb extensions in mice given PTZ. These inhibitors suppressed the percentage of tonic convulsion index and recovery latency for righting reflex in the mice excited with MES. Western blotting demonstrated that Rho translocation to plasma membrane increased in the brain homogenates obtained from PTZ-kindled mice. However, the Rho-kinase inhibitors at the given doses did not change motor coordination of the mice.Conclusions and implications: Rho/Rho-kinase signalling may play a role in epilepsy induced by PTZ and MES. Furthermore, Rho-kinase inhibitors could be novel important antiepileptic agents.