Epileptic brain fluorescent imaging reveals apigenin can relieve the myeloperoxidase-mediated oxidative stress and inhibit ferroptosis
Epileptic brain fluorescent imaging reveals apigenin can relieve the myeloperoxidase-mediated oxidative stress and inhibit ferroptosis
复制标题
癫痫脑荧光成像显示芹菜素可以缓解髓过氧化物酶介导的氧化应激并抑制铁死亡
DOI：
10.1073/pnas.1917946117
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发表时间：
2020-05-12
影响因子：
11.1
通讯作者：
Qian, Yong
中科院分区：
文献类型：
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作者：
Shao, Chenwen;Yuan, Jiwen;Qian, Yong
髓过氧化物酶（MPO）介导的氧化应激被认为在癫痫脑的病理功能障碍中发挥重要作用。然而，目前还没有强大的脑成像工具来检测MPO或荧光探针的实时内源性次氯酸盐（HClO）生成，用于快速高通量筛选控制MPO介导的氯化应激的抗癫痫药物。在此，我们报告了一种高效的双光子荧光探针（命名为HCP）的实时检测内源性HClO信号产生的MPO在红藻氨酸（KA）诱导的癫痫小鼠的大脑中，其中HClO依赖的喹诺酮类荧光团的氯化给增强的荧光响应。用这种探针，我们直接可视化的内源性HClO流量产生的MPO活性在体内和离体在小鼠脑癫痫行为的过度表达。值得注意的是，通过使用HCP，我们还构建了一个高通量筛选方法，以快速筛选潜在的抗癫痫药物来控制MPO介导的氧化应激。此外，从这个筛选，我们确定了黄酮类化合物芹菜素可以减轻MPO介导的氧化应激和抑制神经细胞的铁凋亡。总体而言，这项工作提供了一个通用的荧光工具，用于阐明MPO在癫痫发作的病理学中产生HClO的作用，并快速发现其他抗癫痫药物，以预防和治疗癫痫。
Myeloperoxidase (MPO)-mediated oxidative stress has been suggested to play an important role in the pathological dysfunction of epileptic brains. However, there is currently no robust brain-imaging tool to detect real-time endogenous hypochlorite (HClO) generation by MPO or a fluorescent probe for rapid high-throughput screening of antiepileptic agents that control the MPO-mediated chlorination stress. Herein, we report an efficient two-photon fluorescence probe (named HCP) for the real-time detection of endogenous HClO signals generated by MPO in the brain of kainic acid (KA)-induced epileptic mice, where HClO-dependent chlorination of quinolone fluorophore gives the enhanced fluorescence response. With this probe, we visualized directly the endogenous HClO fluxes generated by the overexpression of MPO activity in vivo and ex vivo in mouse brains with epileptic behaviors. Notably, by using HCP, we have also constructed a high-throughput screening approach to rapidly screen the potential antiepileptic agents to control MPO-mediated oxidative stress. Moreover, from this screen, we identified that the flavonoid compound apigenin can relieve the MPO-mediated oxidative stress and inhibit the ferroptosis of neuronal cells. Overall, this work provides a versatile fluorescence tool for elucidating the role of HClO generation by MPO in the pathology of epileptic seizures and for rapidly discovering additional antiepileptic agents to prevent and treat epilepsy.