Integrated Internal Medicine, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China.
Department of Intensive Care Unit, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530000, People's Republic of China.
Drug Des Devel Ther. 2020 Mar 12;14:1107-1115. doi: 10.2147/DDDT.S231980. eCollection 2020.
Mitochondria play a critical role as effectors and targets of brain injury in the post-resuscitation period. Although we found previously that the extracellular signal-regulated kinase (ERK)1/2 inhibitor PD98059 (PD) protects the brain against mitochondrial-mediated cell death at 24 h post-resuscitation in rats subjected to cardiac arrest/cardiopulmonary resuscitation (CA/CPR), it is not clear whether PD also exerts mitochondrial protective effect for a lasting time. Therefore, we examined the effect of PD on brain mitochondria at 48 h post-resuscitation to evaluate the time-effect of PD in the current study.
Experimental rats were divided randomly into 5 groups: Sham, CA, dimethylsulfoxide (DMSO), 0.15mg/kg PD and 0.3mg/kg PD. Rats except for sham group were subjected to CA for 6 min followed by CPR. We detected survival rates and neurologic deficit scores, cerebral cortex mitochondrial function by evaluating adenosine triphosphate (ATP) levels, mitochondrial permeability transition pore (MPTP) opening, and the expression of mitofusin2 (Mfn2) and observing the ultrastructure by electron microscopy at 48 h post-resuscitation in a 6-min CA rat model.
PD improved survival rates and neurologic deficit scores, alleviated cerebral cortex mitochondrial damage by reducing MPTP opening and increasing Mfn2 production at 48 h post-resuscitation in a 6-min CA rat model.
A single dose of PD improved 48 h post-resuscitation outcome and mitochondrial function, indicating the potential of the use of ERK inhibitors for the treatment of brain injury resulting from CA in the future.
线粒体在心脏骤停/心肺复苏（CA/CPR）后再灌注期作为脑损伤的效应器和靶点起着至关重要的作用。尽管我们之前发现细胞外信号调节激酶（ERK）1/2 抑制剂 PD98059（PD）可在再灌注后 24 小时保护大鼠的大脑免受线粒体介导的细胞死亡，但尚不清楚 PD 是否还会产生持久的线粒体保护作用。因此，我们在再灌注后 48 小时观察 PD 对脑线粒体的影响，以评估 PD 在当前研究中的时间效应。
实验大鼠随机分为 5 组：假手术组、CA 组、二甲基亚砜（DMSO）组、0.15mg/kg PD 组和 0.3mg/kg PD 组。除假手术组外，其余大鼠均进行 6 分钟 CA 后进行 CPR。我们在 6 分钟 CA 大鼠模型中检测了再灌注后 48 小时的存活率和神经功能缺损评分、大脑皮质线粒体功能（通过评估三磷酸腺苷（ATP）水平、线粒体通透性转换孔（MPTP）开放以及观察超微结构来评估），并检测了线粒体融合蛋白 2（Mfn2）的表达。
PD 可改善再灌注后 48 小时的生存率和神经功能缺损评分，减轻大脑皮质线粒体损伤，降低 MPTP 开放，增加 Mfn2 的产生。
单次剂量的 PD 可改善再灌注后 48 小时的预后和线粒体功能，这表明 ERK 抑制剂在未来有治疗 CA 引起的脑损伤的潜力。
