Danchunok Company, Chuncheon, Gangwon, 24210, Republic of Korea.
Department of Biochemistry and Molecular Biology, and Research Institute of Oral Sciences, College of Dentistry, Kangnung-Wonju National University, Gangneung, Gangwon, 25457, Republic of Korea.
Sci Rep. 2019 Sep 10;9(1):13032. doi: 10.1038/s41598-019-49623-x.
Abnormal activation of cyclin-dependent kinase 5 (Cdk5) is associated with pathophysiological conditions. Ischemic preconditioning (IPC) can provide neuroprotective effects against subsequent lethal ischemic insult. The objective of this study was to determine how Cdk5 and related molecules could affect neuroprotection in the hippocampus of gerbils after with IPC [a 2-min transient cerebral ischemia (TCI)] followed by 5-min subsequent TCI. Hippocampal CA1 pyramidal neurons were dead at 5 days post-TCI. However, treatment with roscovitine (a potent inhibitor of Cdk5) and IPC protected CA1 pyramidal neurons from TCI. Expression levels of Cdk5, p25, phospho (p)-Rb and p-p53 were increased in nuclei of CA1 pyramidal neurons at 1 and 2 days after TCI. However, these expressions were attenuated by roscovitine treatment and IPC. In particular, Cdk5, p-Rb and p-p53 immunoreactivities in their nuclei were decreased. Furthermore, TUNEL-positive CA1 pyramidal neurons were found at 5 days after TCI with increased expression levels of Bax, PUMA, and activated caspase-3. These TUNEL-positive cells and increased molecules were decreased by roscovitine treatment and IPC. Thus, roscovitine treatment and IPC could protect CA1 pyramidal neurons from TCI through down-regulating Cdk5, p25, and p-p53 in their nuclei. These findings indicate that down-regulating Cdk5 might be a key strategy to attenuate p53-dependent apoptosis of CA1 pyramidal neurons following TCI.
周期蛋白依赖性激酶 5（Cdk5）的异常激活与病理生理状况有关。缺血预处理（IPC）可以提供针对随后致命性缺血性损伤的神经保护作用。本研究的目的是确定 Cdk5 和相关分子如何在随后的 5 分钟短暂性脑缺血（TCI）后，通过 IPC（2 分钟短暂性脑缺血）影响沙土鼠海马中的神经保护作用。TCI 后 5 天，海马 CA1 锥体神经元死亡。然而，用罗克洛汀（Cdk5 的一种有效抑制剂）和 IPC 处理可保护 CA1 锥体神经元免受 TCI 损伤。TCI 后 1 天和 2 天，CA1 锥体神经元核中 Cdk5、p25、磷酸化（p）-Rb 和 p-p53 的表达水平增加。然而，这些表达被罗克洛汀处理和 IPC 减弱。特别是，核中 Cdk5、p-Rb 和 p-p53 的免疫反应性降低。此外，TCI 后 5 天发现 TUNEL 阳性 CA1 锥体神经元，Bax、PUMA 和活化的 caspase-3 的表达水平增加。这些 TUNEL 阳性细胞和增加的分子被罗克洛汀处理和 IPC 减少。因此，罗克洛汀处理和 IPC 可通过下调核中 Cdk5、p25 和 p-p53 来保护 CA1 锥体神经元免受 TCI 损伤。这些发现表明，下调 Cdk5 可能是减轻 TCI 后 CA1 锥体神经元中 p53 依赖性细胞凋亡的关键策略。
