Preconditioning induces sustained neuroprotection by downregulation of adenosine 5'-monophosphate-activated protein kinase.
Preconditioning induces sustained neuroprotection by downregulation of adenosine 5'-monophosphate-activated protein kinase.
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DOI：
10.1016/j.neuroscience.2011.11.014
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发表时间：
2012-01-10
期刊：
影响因子：
3.3
通讯作者：
McCullough LD
中科院分区：
文献类型：
--
作者：
Venna VR;Li J;Benashski SE;Tarabishy S;McCullough LD
缺血预适应（IPC）可诱导内源性神经保护免受随后的缺血性损伤。 IPC 涉及代谢途径的下调。由于 5'-单磷酸腺苷激活蛋白激酶 (AMPK) 是能量平衡的关键传感器并在细胞代谢中发挥重要作用，因此对其在 IPC 中的作用进行了研究。在 90 分钟 MCAO 之前 72 小时，采用短暂的 3 分钟大脑中动脉闭塞 (MCAO) 来诱导雄性小鼠 IPC。 IPC 后评估 AMPK 和 pAMPK（激酶的活性形式）的水平。利用 AMPK 的药理学激活剂或抑制剂来确定 IPC 对 AMPK 信号传导的依赖性。此外，对 AMPK-α2 缺失小鼠进行 IPC 并评估随后的梗塞损伤。 IPC 诱导神经保护、增强 HSP70 并改善行为结果。这些有益效果与 pAMPK 蛋白表达的显着抑制同时发生。尽管 AMPK 或 IPC 的药理学抑制都会产生神经保护作用，但当与 AMPK 抑制剂共同给药时，IPC 没有提供额外的保护作用。此外，二甲双胍对 AMPK 的药理学激活消除了 IPC 的神经保护作用。缺乏 AMPK 催化亚型的 AMPK-α2 缺失小鼠未能表现出预处理反应。 AMPK 的调节在 IPC 介导的神经保护中发挥重要作用。 AMPK可能是治疗脑缺血的潜在治疗靶点。
Ischemic preconditioning (IPC) induces endogenous neuroprotection from a subsequent ischemic injury. IPC involves down-regulation of metabolic pathways. As Adenosine 5′-monophosphate-activated protein kinase (AMPK) is a critical sensor of energy balance and plays a major role in cellular metabolism, its role in IPC was investigated. A brief 3 minute middle cerebral artery occlusion (MCAO) was employed to induce IPC in male mice 72 hours prior to 90 minute MCAO. Levels of AMPK and pAMPK, the active form of the kinase, were assessed after IPC. A pharmacological activator or inhibitor of AMPK was utilized to determine the dependence of IPC on AMPK signaling. Additionally, AMPK-α2 null mice were subjected to IPC and subsequent infarct damage was assessed. IPC induced neuroprotection, enhanced HSP70 and improved behavioral outcomes. These beneficial effects occurred in parallel with a significant inhibition of pAMPK protein expression. Although both pharmacological inhibition of AMPK or IPC led to neuroprotection, IPC offered no additional protective effects when co-administered with an AMPK inhibitor. Moreover, pharmacological activation of AMPK with Metformin abolished the neuroprotective effects of IPC. AMPK-α2 null mice that lack the catalytic isoform of AMPK failed to demonstrate a preconditioning response. Regulation of AMPK plays an important role in IPC mediated neuroprotection. AMPK may be a potential therapeutic target for the treatment of cerebral ischemia.
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DOI：
10.1038/jcbfm.2009.255
发表时间：
2010-03
期刊：
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.8
作者：
Vingtdeux, Valerie;Chandakkar, Pallavi;Marambaud, Philippe
通讯作者：
Marambaud, Philippe
DOI：
10.1053/j.jvca.2010.02.007
发表时间：
2011-02-01
影响因子：
2.8
作者：
Lotz, Christopher;Fisslthaler, Beate;Lange, Markus
通讯作者：
Lange, Markus
影响因子：
5
作者：
Puisieux, F;Deplanque, D;Bordet, R
通讯作者：
Bordet, R
影响因子：
10.8
作者：
Nishino, Y;Miura, T;Shimamoto, K
通讯作者：
Shimamoto, K