Carbon monoxide-releasing molecule-3 protects against cortical pyroptosis induced by hemorrhagic shock and resuscitation via mitochondrial regulation.
Carbon monoxide-releasing molecule-3 protects against cortical pyroptosis induced by hemorrhagic shock and resuscitation via mitochondrial regulation.
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DOI：
10.1016/j.freeradbiomed.2019.06.031
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发表时间：
2019-09
影响因子：
7.4
通讯作者：
Li-Min Zhang;Dongxue Zhang;Lan Fu;Yan Li;Xu-Peng Wang;Man-Man Qi-Man;Chen-Chen Li-Chen;Panpan Song
中科院分区：
文献类型：
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作者：
Li-Min Zhang;Dongxue Zhang;Lan Fu;Yan Li;Xu-Peng Wang;Man-Man Qi-Man;Chen-Chen Li-Chen;Panpan Song
CORM-3是一种水溶性的CORM，具有抗炎和抗缺血/再灌注损伤的作用。我们确定的效果CORM-3对神经元pyroptosis在模型中的失血性休克和复苏（HSR）在rats通过mitochondrial regulation.MethodsRats在体外处理CORM-3（4 mg/kg）后HSR。我们测量皮质CO含量3-24小时后HSR;评估神经元焦亡，线粒体形态，ROS的生产，和线粒体膜电位在12小时后HSR;和评估脑磁共振成像在24小时后HSR和学习能力30天后HSR。我们还测量了可溶性鸟苷酸环化酶（sGC）-环磷酸鸟苷（cGMP）信号通路的活动，使用sGC，NS 2028，and125 I-cGMP assay.ResultsAmong大鼠进行HSR，CORM-3治疗的大鼠有更多的CO皮质组织比假手术和iCORM-3治疗的大鼠。CORM-3处理的大鼠皮质组织中神经元的焦亡显著减少; sGC活性和cGMP含量更高; ROS产生更低;线粒体形态、功能和膜电位更好;学习/记忆能力比HSR处理的大鼠增强。结论CORM-3可能通过sGC-cGMP途径介导的线粒体调节作用减轻HSR大鼠神经元凋亡，促进神经功能恢复。因此，CO给药可能是一种有前途的失血性休克治疗策略。
ObjectiveCarbon monoxide (CO) releasing molecule (CORM)-3, a water-soluble CORM, has protective effects against inflammatory and ischemia/reperfusion injury. We determined the effect of CORM-3 against neuronal pyroptosis in a model of hemorrhagic shock and resuscitation (HSR) in rats via mitochondrial regulation.MethodsRats were treated with CORM-3 (4 mg/kg) in vitro after HSR. We measured cortical CO content 3–24 h after HSR; assessed neuronal pyroptosis, mitochondrial morphology, ROS production, and mitochondrial membrane potential at 12 h after HSR; and evaluated brain magnetic resonance imaging at 24 h after HSR and learning ability 30 days after HSR. We also measured soluble guanylate-cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway activity using a blocker of sGC, NS2028, and125I-cGMP assay.ResultsAmong rats that underwent HSR, CORM-3-treated rats had more CO in the cortical tissue than sham- and iCORM-3-treated rats. CORM-3-treated rats had significantly less neuronal pyroptosis in the cortical tissue; higher sGC activity and cGMP content; lower ROS production; better mitochondrial morphology, function, and membrane potential; and enhanced learning/memory ability than HSR-treated rats. However, these neuroprotective effects of CORM-3 were partially inhibited by NS2028.ConclusionCORM-3 may alleviate neuronal pyroptosis and improve neurological recovery in HSR through mitochondrial regulation mediated by the sGC–cGMP pathway. Thus, CO administration could be a promising therapeutic strategy for hemorrhagic shock.