Mild cerebral ischemia induces loss of cyclin-dependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death
Mild cerebral ischemia induces loss of cyclin-dependent kinase inhibitors and activation of cell cycle machinery before delayed neuronal cell death
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DOI：
10.1523/jneurosci.21-14-05045.2001
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发表时间：
2001-07-15
影响因子：
5.3
通讯作者：
Endres, M
中科院分区：
文献类型：
--
作者：
Katchanov, J;Harms, C;Endres, M
在轻度缺血损伤后，许多神经元发生迟发性神经元死亡。细胞周期机制的异常激活被认为有助于包括缺血在内的各种条件下的细胞凋亡。我们证明，内源性细胞周期蛋白依赖性激酶（Cdk）抑制剂p16（INK 4a）的损失是一个早期和可靠的指标，在纹状体神经元迟发性神经元死亡后，轻度脑缺血在体内。另一种Cdk抑制剂p27（Kip 1）的缺失先于体外氧-葡萄糖剥夺的新皮层神经元的细胞死亡。Cdk抑制剂的丧失之后是细胞周期蛋白D1的上调、Cdk 2的活化和随后的细胞骨架解体。大多数神经元在进入S期之前经历细胞死亡，尽管少数（大约1%）在死亡之前确实进展到S期。用Cdk抑制剂处理显著减少体外细胞死亡。这些结果表明，细胞周期调控机制的改变是局灶性脑缺血迟发性神经元死亡的前奏，旨在神经保护的药理学干预可能是有用的细胞周期调控机制。
After mild ischemic insults, many neurons undergo delayed neuronal death. Aberrant activation of the cell cycle machinery is thought to contribute to apoptosis in various conditions including ischemia. We demonstrate that loss of endogenous cyclin-dependent kinase (Cdk) inhibitor p16(INK4a) is an early and reliable indicator of delayed neuronal death in striatal neurons after mild cerebral ischemia in vivo. Loss of p27(Kip1), another Cdk inhibitor, precedes cell death in neocortical neurons subjected to oxygen-glucose deprivation in vitro. The loss of Cdk inhibitors is followed by upregulation of cyclin D1, activation of Cdk2, and subsequent cytoskeletal disintegration. Most neurons undergo cell death before entering S-phase, albeit a small number (similar to1%) do progress to the S-phase before their death. Treatment with Cdk inhibitors significantly reduces cell death in vitro. These results show that alteration of cell cycle regulatory mechanisms is a prelude to delayed neuronal death in focal cerebral ischemia and that pharmacological interventions aimed at neuroprotection may be usefully directed at cell cycle regulatory mechanisms.