Pharmacological inhibition of AMP-activated protein kinase provides neuroprotection in stroke
Pharmacological inhibition of AMP-activated protein kinase provides neuroprotection in stroke
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DOI：
10.1074/jbc.m409985200
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发表时间：
2005-05-27
影响因子：
4.8
通讯作者：
Ronnett, GV
中科院分区：
文献类型：
--
作者：
McCullough, LD;Zeng, ZY;Ronnett, GV
在缺血期间恢复能量平衡对细胞存活至关重要；然而，对于中枢神经系统缺血时神经元代谢途径的调节知之甚少。AMP活化蛋白激酶（AMPK）是外周组织中能量平衡的主要传感器，当能量平衡较低时会被磷酸化并激活。我们研究了AMPK在缺血期间是否也可能调节神经元的能量稳态。我们利用两种缺血模型系统，即体内大脑中动脉闭塞和体外氧 - 葡萄糖剥夺，来描绘由代谢应激引起的AMPK活性变化。在正常和缺血条件下，AMPK在皮质和海马神经元中均高度表达。通过磷酸化状态评估，大脑中动脉闭塞和氧 - 葡萄糖剥夺后AMPK活性均增加。已知的神经元ATP水平调节剂C75或化合物C对AMPK的药理抑制可减轻中风损伤。相反，5 - 氨基咪唑 - 4 - 羧酰胺核糖核苷激活AMPK会加剧损伤。与野生型相比，神经元一氧化氮合酶缺陷小鼠的中风损伤和AMPK激活均降低，这表明在中风中NO和AMPK激活之间可能存在相互作用。这些数据表明AMPK在代谢应激期间神经元的反应中起作用，并提示在缺血时AMPK的激活是有害的。在缺血期间通过药理学手段调控神经元能量平衡的能力代表了一种神经保护的创新方法。
The restoration of energy balance during ischemia is critical to cellular survival; however, relatively little is known concerning the regulation of neuronal metabolic pathways in response to central nervous system ischemia. AMP-activated protein kinase ( AMPK), a master sensor of energy balance in peripheral tissues, is phosphorylated and activated when energy balance is low. We investigated whether AMPK might also modulate neuronal energy homeostasis during ischemia. We utilized two model systems of ischemia, middle cerebral artery occlusion in vivo and oxygen-glucose deprivation in vitro, to delineate changes in AMPK activity incurred from a metabolic stress. AMPK is highly expressed in cortical and hippocampal neurons under both normal and ischemic conditions. AMPK activity, as assessed by phosphorylation status, is increased following both middle cerebral artery occlusion and oxygen-glucose deprivation. Pharmacological inhibition of AMPK by either C75, a known modulator of neuronal ATP levels, or compound C reduced stroke damage. In contrast, activation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleoside exacerbated damage. Mice deficient in neuronal nitric-oxide synthase demonstrated a decrease in both stroke damage and AMPK activation compared with wild type, suggesting a possible interaction between NO and AMPK activation in stroke. These data demonstrate a role for AMPK in the response of neurons during metabolic stress and suggest that in ischemia the activation of AMPK is deleterious. The ability to manipulate pharmacologically neuronal energy balance during ischemia represents an innovative approach to neuroprotection.