Min Su-Ji, Hyun Hye-Won, Kang Tae-Cheon
Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chunchon 24252, South Korea; Institute of Epilepsy Research, College of Medicine, Hallym University, Chunchon 24252, South Korea.
Department of Anatomy and Neurobiology, College of Medicine, Hallym University, Chunchon 24252, South Korea; Institute of Epilepsy Research, College of Medicine, Hallym University, Chunchon 24252, South Korea.
Brain Res. 2017 Sep 1;1670:14-23. doi: 10.1016/j.brainres.2017.06.002. Epub 2017 Jun 7.
Leptomycin B (LMB), originally developed as an anti-fungal agent, has potent neuroprotective properties against status epilepticus (SE, a prolonged seizure activity). However, the pharmacological profiles and mechanisms of LMB for neuroprotection remain elusive. In the present study, we found that LMB increased phosphorylation levels of protein kinase A (PKA) catalytic subunits, protein phosphatase 2B (PP2B, calcineurin) and extracellular signal-regulated kinase 1/2 (ERK1/2) under normal condition, and abolished SE-induced neuronal death. Co-treatment of H-89 (a PKA inhibitor) with LMB could not affect the seizure latency and its severity in response to pilocarpine. However, H-89 co-treatment abrogated the protective effect of LMB on SE-induced neuronal damage. Cyclosporin A (CsA, a PP2B inhibitor) co-treatment effectively prevented SE-induced neuronal death without altered seizure susceptibility in response to pilocarpine more than LMB alone. H-89 co-treatment inhibited LMB-mediated ERK1/2 phosphorylation, but CsA enhanced it. U0126 (an ERK1/2 inhibitor) co-treatment abolished the protective effect of LMB on SE-induced neuronal death without alterations in PKA and PP2B phosphorylations. To the best of our knowledge, the present data demonstrate a previously unreported potential neuroprotective role of LMB against SE via PKA- and PP2B-mediated ERK1/2 activation.
细霉素B（LMB）最初是作为一种抗真菌剂开发的，对癫痫持续状态（SE，一种长时间的癫痫发作活动）具有强大的神经保护特性。然而，LMB神经保护的药理特性和机制仍不清楚。在本研究中，我们发现LMB在正常条件下增加蛋白激酶A（PKA）催化亚基、蛋白磷酸酶2B（PP2B，钙调神经磷酸酶）和细胞外信号调节激酶1/2（ERK1/2）的磷酸化水平，并消除SE诱导的神经元死亡。H-89（一种PKA抑制剂）与LMB联合处理不影响对毛果芸香碱的癫痫发作潜伏期及其严重程度。然而，H-89联合处理消除了LMB对SE诱导的神经元损伤的保护作用。环孢素A（CsA，一种PP2B抑制剂）联合处理比单独使用LMB更有效地预防了SE诱导的神经元死亡，而不改变对毛果芸香碱的癫痫易感性。H-89联合处理抑制LMB介导的ERK1/2磷酸化，但CsA增强了它。U0126（一种ERK1/2抑制剂）联合处理消除了LMB对SE诱导的神经元死亡的保护作用，而不改变PKA和PP2B的磷酸化。据我们所知，目前的数据表明LMB通过PKA和PP2B介导的ERK1/2激活对SE具有以前未报道的潜在神经保护作用。
