Mechanism of Action and Translational Potential of (S)-Meclizine in Preemptive Prophylaxis Against Stroke.
Mechanism of Action and Translational Potential of (S)-Meclizine in Preemptive Prophylaxis Against Stroke.
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(S)-Meclizine 在中风预防中的作用机制和转化潜力。
DOI：
10.1161/strokeaha.123.044397
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发表时间：
2024
期刊：
影响因子：
8.3
通讯作者：
Ayata,Cenk
中科院分区：
文献类型：
--
作者：
Lee,JeongHyun;Gohil,VishalM;Heidari,Pedram;Seidel,JessicaL;Zulkifli,Mohammad;Wei,Ying;Ji,Yuhua;Daneshmand,Ali;Mahmood,Umar;Clish,ClaryB;Mootha,VamsiK;Ayata,Cenk
线粒体呼吸的轻度化学抑制可以赋予对随后的中风或心肌梗死的恢复力，也称为预适应。然而，缺乏能够安全抑制线粒体呼吸的化学物质阻碍了预处理概念的临床转化。我们以前发现，美克洛嗪，一种非处方抗眩晕药物，可以将代谢从线粒体呼吸转换为糖酵解，并保护大脑，心脏和肾脏免受缺血再灌注损伤。在这里，我们研究的作用机制，美克洛嗪和报告的有效性和改善的安全性（S）对映体。METHODSWe确定缺氧去极化潜伏期，组织和神经系统的结果，和葡萄糖摄取后，使用微正电子发射断层扫描短暂大脑中动脉闭塞的小鼠预处理（-17和-3小时）与车辆或美克洛嗪。为了排除对组织兴奋性的直接影响，我们还研究了扩散性抑制易感性。此外，我们完成了（R）-和（S）-美克洛嗪的手性合成，并比较了它们对耗氧量和组胺H1受体结合沿着其脑concentration. Micro-positron发射断层扫描显示，美克洛嗪增加缺血半影区的葡萄糖摄取，提供了第一个体内证据，证明美克洛嗪的神经保护作用确实源于其将代谢转换为糖酵解的能力。与依赖氧化磷酸化来维持代谢的减少一致，美克洛嗪延迟了大脑中动脉闭塞后缺氧去极化的发生。此外，（S）对映异构体显示H1受体结合减少，这是外消旋体的剂量限制性副作用，但保留了其对线粒体呼吸的影响。（S）-美克洛嗪是至少一样有效的raccavity在延迟缺氧去极化发作和减少梗死体积后大脑中动脉occlusion.CONCLUSIONSOUR的数据确定（S）-美克洛嗪作为一个有前途的新的候选药物，具有高翻译潜力的化学预处理剂，用于先发制人的预防高迫在眉睫的中风或心肌梗死的风险。
BACKGROUNDMild chemical inhibition of mitochondrial respiration can confer resilience against a subsequent stroke or myocardial infarction, also known as preconditioning. However, the lack of chemicals that can safely inhibit mitochondrial respiration has impeded the clinical translation of the preconditioning concept. We previously showed that meclizine, an over-the-counter antivertigo drug, can toggle metabolism from mitochondrial respiration toward glycolysis and protect against ischemia-reperfusion injury in the brain, heart, and kidney. Here, we examine the mechanism of action of meclizine and report the efficacy and improved safety of the(S) enantiomer.METHODSWe determined the anoxic depolarization latency, tissue and neurological outcomes, and glucose uptake using micro–positron emission tomography after transient middle cerebral artery occlusion in mice pretreated (−17 and −3 hours) with either vehicle or meclizine. To exclude a direct effect on tissue excitability, we also examined spreading depression susceptibility. Furthermore, we accomplished the chiral synthesis of(R)- and(S)-meclizine and compared their effects on oxygen consumption and histamine H1 receptor binding along with their brain concentrations.RESULTSMicro–positron emission tomography showed meclizine increases glucose uptake in the ischemic penumbra, providing the first in vivo evidence that the neuroprotective effect of meclizine indeed stems from its ability to toggle metabolism toward glycolysis. Consistent with reduced reliance on oxidative phosphorylation to sustain the metabolism, meclizine delayed anoxic depolarization onset after middle cerebral artery occlusion. Moreover, the(S) enantiomer showed reduced H1 receptor binding, a dose-limiting side effect for the racemate, but retained its effect on mitochondrial respiration.(S)-meclizine was at least as efficacious as the racemate in delaying anoxic depolarization onset and decreasing infarct volumes after middle cerebral artery occlusion.CONCLUSIONSOur data identify(S)-meclizine as a promising new drug candidate with high translational potential as a chemical preconditioning agent for preemptive prophylaxis in patients with high imminent stroke or myocardial infarction risk.