Pharmacological Validation of ASIC1a as a Druggable Target for Neuroprotection in Cerebral Ischemia Using an Intravenously Available Small Molecule Inhibitor.
Pharmacological Validation of ASIC1a as a Druggable Target for Neuroprotection in Cerebral Ischemia Using an Intravenously Available Small Molecule Inhibitor.
复制标题
使用静脉注射小分子抑制剂对 ASIC1a 作为脑缺血神经保护的药物靶点进行药理学验证
DOI：
10.3389/fphar.2022.849498
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发表时间：
2022
影响因子：
5.6
通讯作者：
Xu TL
中科院分区：
文献类型：
--
作者：
Qi X;Lu JF;Huang ZY;Liu YJ;Cai LB;Wen XL;Song XL;Xiong J;Sun PY;Zhang H;Zhang TT;Zhao X;Jiang Q;Li Y;Krishtal O;Hou LC;Zhu MX;Xu TL
酸中毒是缺血性中风的一个特征，也是预防神经元损伤颇具前景的神经保护靶点。此前，基因操作研究表明，阻断酸敏感离子通道1a（ASIC1a）介导的酸毒性，可显著减轻脑梗死体积，并在脑缺血后恢复神经功能。然而，几乎没有已确定的药理学候选药物能通过抑制ASIC1a对缺血性中风发挥疗效。在这项研究中，我们检测了一种受毒素启发合成的化合物5b（C5b）在体内缺血性中风动物模型中发挥保护作用的能力，此前研究发现该化合物在体外能有效抑制ASIC1a。我们发现，C5b不仅在体外酸诱导的神经元死亡模型中，而且在体内缺血性脑损伤模型中，均发挥了显著的神经保护作用，这表明ASIC1a是一个可用于药物研发的靶点。更重要的是，在缺血动物模型中静脉注射C5b后，它能够穿过血脑屏障并显著减小脑梗死体积，这突出了其在治疗酸毒性所致神经退行性疾病方面的全身可用性。总之，我们的数据表明，C5b是一种很有前景的通过抑制ASIC1a发挥神经保护作用的先导化合物，值得进一步开展转化研究。
Acidosis is a hallmark of ischemic stroke and a promising neuroprotective target for preventing neuronal injury. Previously, genetic manipulations showed that blockade of acid-sensing ion channel 1a (ASIC1a)-mediated acidotoxicity could dramatically alleviate the volume of brain infarct and restore neurological function after cerebral ischemia. However, few pharmacological candidates have been identified to exhibit efficacy on ischemic stroke through inhibition of ASIC1a. In this work, we examined the ability of a toxin-inspired compound 5b (C5b), previously found to effectively inhibit ASIC1a in vitro, to exert protective effects in animal models of ischemic stroke in vivo. We found that C5b exerts significant neuroprotective effects not only in acid-induced neuronal death in vitro but also ischemic brain injury in vivo, suggesting that ASIC1a is a druggable target for therapeutic development. More importantly, C5b is able to cross the blood brain barrier and significantly reduce brain infarct volume when administered intravenously in the ischemic animal model, highlighting its systemic availability for therapies against neurodegeneration due to acidotoxicity. Together, our data demonstrate that C5b is a promising lead compound for neuroprotection through inhibiting ASIC1a, which warrants further translational studies.
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影响因子：
25
作者：
Kreple, Collin J.;Lu, Yuan;Wemmie, John A.
通讯作者：
Wemmie, John A.
影响因子：
158.5
作者：
Feigin, Valery L.;Nguyen, Grant;Roth, Gregory A.
通讯作者：
Roth, Gregory A.
影响因子：
7.3
作者：
Buta, Andriy;Maximyuk, Oleksandr;Krishtal, Oleg
通讯作者：
Krishtal, Oleg
影响因子：
64.5
作者：
Baconguis I;Bohlen CJ;Goehring A;Julius D;Gouaux E
通讯作者：
Gouaux E
影响因子：
11.2
作者：
O'Collins, VE;Macleod, MR;Howells, DW
通讯作者：
Howells, DW