A novel neuroprotective mechanism of riluzole: Direct inhibition of protein kinase C
A novel neuroprotective mechanism of riluzole: Direct inhibition of protein kinase C
复制标题
DOI：
10.1006/nbdi.2000.0297
复制
发表时间：
2000-08-01
影响因子：
6.1
通讯作者：
Koh, JY
中科院分区：
文献类型：
--
作者：
Noh, KM;Hwang, JY;Koh, JY
除了其抗兴奋性毒性作用，抗肌萎缩侧索硬化症（ALS）神经保护剂利鲁唑还可防止非兴奋性毒性氧化神经元损伤。根据蛋白激酶C（PKC）介导皮质培养中氧化应激的证据，我们研究了利鲁唑的抗氧化神经保护作用涉及PKC抑制的可能性。阿珠唑（30 μ M）阻断佛波酯12-肉豆蔻酸酯13-乙酸酯（PMA）诱导的培养的皮层细胞膜PKC活性的增加。利鲁唑也抑制纯化的PKC的活性，这表明其具有直接作用。结论：利鲁唑可明显减轻PMA诱导的PKC耗竭和氧化性神经元死亡。利鲁唑对PKC的作用位点不太可能是二酰甘油结合位点，而是催化结构域，因为利鲁唑不改变放射性标记的佛波醇-12，13-二丁酸酯结合，但抑制PKC的催化结构域PKM。然而，增加ATP浓度并没有改变利鲁唑对PKC的抑制作用，这使得利鲁唑不太可能是ATP结合PKM的竞争性抑制剂。目前的研究结果表明，利鲁唑直接抑制PKC，这一行动可能有助于其抗氧化神经保护作用。此外，PKC抑制可能能够解释其一些众所周知的通道抑制和神经保护作用。结合ALS中PKC活性增加的发现，本研究结果表明，PKC可能是ALS的潜在治疗靶点。(C)北京大学出版社.
In addition to its antiexcitotoxic action, the anti-amyotrophic lateral sclerosis (ALS) neuroprotectant riluzole protects against nonexcitotoxic oxidative neuronal injury. In light of evidence that protein kinase C (PKC) mediates oxidative stress in cortical culture, we examined the possibility that riluzole's antioxidative neuroprotection involves PKC inhibition. Riluzole (30 mu M) blocked phorbol 12-myristate 13-acetate (PMA)-induced increases in membrane PKC activity in cultured cortical cells. Suggesting a direct action, riluzole also inhibited the activity of purified PKC. Consistently, both PKC depletion and oxidative neuronal death induced by PMA were markedly attenuated by riluzole. The site of action of riluzole on PKC was not likely the diacylglycerol binding site but the catalytic domain, since riluzole did not alter radiolabeled phorbol-12,13-dibutyrate binding, but inhibited PKM, the catalytic domain of PKC. However, increasing ATP concentrations did not alter the inhibition of PKC by riluzole, making it unlikely that riluzole is a competitive inhibitor of ATP binding at PKM. Present results have demonstrated that riluzole directly inhibits PKC, which action may contribute to its antioxidative neuroprotective effects. In addition, it appears possible that PKC inhibition may be able to explain some of its well-known channel inhibitory and neuroprotective effects. Combined with findings that PKC activity is increased in ALS, the present results suggest that PKC may be a potential therapeutic target in ALS. (C) 2000 Academic Press.