Antiepileptic action of c-Jun N-terminal kinase (JNK) inhibition in an animal model of temporal lobe epilepsy.
Antiepileptic action of c-Jun N-terminal kinase (JNK) inhibition in an animal model of temporal lobe epilepsy.
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DOI：
10.1016/j.neuroscience.2017.02.024
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发表时间：
2017-05-04
期刊：
影响因子：
3.3
通讯作者：
Poolos NP
中科院分区：
文献类型：
--
作者：
Tai TY;Warner LN;Jones TD;Jung S;Concepcion FA;Skyrud DW;Fender J;Liu Y;Williams AD;Neumaier JF;D'Ambrosio R;Poolos NP
一些磷酸化信号通路参与了癫痫的发病机制，其原因既有遗传原因，也有后天对大脑的损害。识别癫痫中功能失调的信号通路可能为抗癫痫治疗提供新的靶点。我们之前描述了p38丝裂原活化蛋白激酶(P38 MAPK)介导的磷酸化信号的缺陷，这种缺陷发生在颞叶癫痫的动物模型中，并在体外产生神经元的超兴奋性。我们询问体内对p38 MAPK活性的药理操作是否会影响慢性癫痫动物的癫痫发作频率。给予p38 MAPK抑制剂SB203580显著恶化自发性癫痫发作频率，这与先前的体外结果一致。然而，非特异性p38MAPK激活剂--茴香素可显著增加癫痫发作频率。我们假设这一意外结果是由于相关的MAPK，c-Jun氨基末端激酶(JNK)的激活所致。给予JNK抑制剂SP600125可显著降低癫痫发作频率，且呈剂量依赖关系，且不会引起明显的行为异常。生化分析显示，未经治疗的癫痫动物JNK表达和活性增加。这些结果首次表明JNK在癫痫动物模型中被过度激活，并且JNK介导的磷酸化信号可能代表了一个新的抗癫痫靶点。
Several phosphorylation signaling pathways have been implicated in the pathogenesis of epilepsy arising from both genetic causes and acquired insults to the brain. Identification of dysfunctional signaling pathways in epilepsy may provide novel targets for antiepileptic therapies. We previously described a deficit in phosphorylation signaling mediated by p38 mitogen-activated protein kinase (p38 MAPK) that occurs in an animal model of temporal lobe epilepsy, and that produces neuronal hyperexcitability measured in vitro. We asked whether in vivo pharmacological manipulation of p38 MAPK activity would influence seizure frequency in chronically epileptic animals. Administration of a p38 MAPK inhibitor, SB203580, markedly worsened spontaneous seizure frequency, consistent with prior in vitro results. However, anisomycin, a non-specific p38 MAPK activator, significantly increased seizure frequency. We hypothesized that this unexpected result was due to activation of a related MAPK, c-Jun N-terminal kinase (JNK). Administration of JNK inhibitor SP600125 significantly decreased seizure frequency in a dose-dependent manner without causing overt behavioral abnormalities. Biochemical analysis showed increased JNK expression and activity in untreated epileptic animals. These results show for the first time that JNK is hyperactivated in an animal model of epilepsy, and that phosphorylation signaling mediated by JNK may represent a novel antiepileptic target.