Aspirin prevention of NMDA-induced neuronal death by direct protein kinase Cζ inhibition
Aspirin prevention of NMDA-induced neuronal death by direct protein kinase Cζ inhibition
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DOI：
10.1111/j.1471-4159.2005.03157.x
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发表时间：
2005-06-01
影响因子：
4.7
通讯作者：
Omri, B
中科院分区：
文献类型：
--
作者：
Crisanti, P;Leon, A;Omri, B
阿司匹林已被证明可以通过核因子κ B通路保护谷氨酸神经毒性。一些研究表明，非典型蛋白激酶C（PKC）zeta（zeta）亚型在细胞保护中起作用，但其机制尚不清楚。我们在这里表明，阿司匹林通过PKC zeta发挥至少部分作用，减少NMDA诱导的激活，分裂和核转位的这个分子。阿司匹林（乙酰水杨酸）直接抑制PKC zeta的蛋白激酶活性，而水杨酸没有。阿司匹林对纯化的人PKC zeta的这种直接作用与PKC zeta抑制防止NMDA诱导的皮质神经元死亡一致。Caspase-3抑制阻断了PKC zeta的裂解和核转位，而Caspase-1抑制没有。因此，PKC ζ（蛋白激酶M ζ）调节细胞凋亡途径起始所必需的核事件。阿司匹林通过一种靶向PKC zeta的新机制保护细胞免受NMDA诱导的凋亡，PKC zeta是炎症反应和神经退行性变的关键分子。
Aspirin has been shown to protect against glutamate neurotoxicity via the nuclear factor kappa B pathway. Some studies have implicated the atypical protein kinase C (PKC) zeta (zeta) isoform in cell protection, but the mechanism involved remains unclear. We show here that aspirin exerts at least some of its effects through PKC zeta, decreasing the NMDA-induced activation, cleavage and nuclear translocation of this molecule. Aspirin (acetylsalicylic acid) directly inhibited the protein kinase activity of PKC zeta, whereas salicylic acid did not. This direct effect of aspirin on purified human PKC zeta is consistent with PKC zeta inhibition preventing the NMDA-induced death of cortical neurones. Caspase-3 inhibition blocked the cleavage and nuclear translocation of PKC zeta, whereas caspase-1-inhibition did not. Thus, PKC zeta (protein kinase M zeta) regulates nuclear events essential for the initiation of the apoptotic pathway. Aspirin protects cells against NMDA-induced apoptosis by means of a novel mechanism targeting PKC zeta, a key molecule in inflammatory responses and neurodegeneration.