Pulse inhibition of histone deacetylases induces complete resistance to oxidative death in cortical neurons without toxicity and reveals a role for cytoplasmic p21waf1/cip1 in cell cycle-independent neuroprotection
Pulse inhibition of histone deacetylases induces complete resistance to oxidative death in cortical neurons without toxicity and reveals a role for cytoplasmic p21waf1/cip1 in cell cycle-independent neuroprotection
复制标题
DOI：
10.1523/jneurosci.3200-07.2008
复制
发表时间：
2008-01-02
影响因子：
5.3
通讯作者：
Ratan, Rajiv R.
中科院分区：
文献类型：
--
作者：
Langley, Brett;D'Annibale, Melissa A.;Ratan, Rajiv R.
组蛋白脱乙酰酶 (HDAC) 抑制剂目前作为抗肿瘤药物正在进行人体临床试验，因为它们能够诱导癌细胞功能障碍和死亡。 HDAC 抑制剂的毒性作用在体外皮质神经元中也很明显，尽管这些药物能够在它们不杀死的细胞中诱导显着的保护作用。在这里，我们证明在体外氧化应激模型中皮层神经元的脉冲暴露（2小时）可产生持久的神经保护而无毒性。在该模型和永久缺血体内模型中，保护作用与细胞周期抑制剂 p21(waf1/cip1) 的转录上调有关。神经元中 p21(waf1/cip1) 的转基因过表达可以模拟 HDAC 抑制剂对氧化应激诱导的毒性的保护作用，包括谷胱甘肽耗尽或过氧化物添加诱导的死亡。 p21(waf1/cip1) 在氧化应激背景下的保护作用似乎与其在细胞核中抑制细胞周期进程的能力无关。然而，虽然p21(waf1/cip1)足以提供神经保护作用，但HDAC抑制剂的神经保护作用并不是必需的，因为这些药物可以完全保护从p21(waf1/cip1)缺失小鼠培养的神经元。这些发现共同证明：（1）皮层神经元中 HDAC 的脉冲抑制可以诱导神经保护，而没有明显的毒性； (2) p21(waf1/cip1)足以但不是模拟 HDAC 抑制的保护作用所必需的； (3) 该模型中的氧化应激通过细胞周期独立途径诱导神经元细胞死亡，该途径可被 p21(waf1/cip1) 的胞质非典型作用抑制。
Histone deacetylase (HDAC) inhibitors are currently in human clinical trials as antitumor drugs because of their ability to induce cell dysfunction and death in cancer cells. The toxic effects of HDAC inhibitors are also apparent in cortical neurons in vitro, despite the ability of these agents to induce significant protection in the cells they do not kill. Here we demonstrate that pulse exposure of cortical neurons (2h) in an in vitro model of oxidative stress results in durable neuroprotection without toxicity. Protection was associated with transcriptional upregulation of the cell cycle inhibitor, p21(waf1/cip1), both in this model and in an in vivo model of permanent ischemia. Transgenic overexpression of p21(waf1/cip1) in neurons can mimic the protective effect of HDAC inhibitors against oxidative stress-induced toxicity, including death induced by glutathione depletion or peroxide addition. The protective effect of p21(waf1/cip1) in the context of oxidative stress appears to be unrelated to its ability to act in the nucleus to inhibit cell cycle progression. However, although p21(waf1/cip1) is sufficient for neuroprotection, it is not necessary for HDAC inhibitor neuroprotection, because these agents can completely protect neurons cultured from p21(waf1/cip1)-null mice. Together these findings demonstrate (1) that pulse inhibition of HDACs in cortical neurons can induce neuroprotection without apparent toxicity; (2) that p21(waf1/cip1) is sufficient but not necessary to mimic the protective effects of HDAC inhibition; and ( 3) that oxidative stress in this model induces neuronal cell death via cell cycle-independent pathways that can be inhibited by a cytosolic, noncanonical action of p21(waf1/cip1).