Wang Peng, Li Ying, Yan Baihui, Yang Zhong, Li Litao, Cao Zhipeng, Li Xuan, Batinic-Haberle Ines, Spasojevic Ivan, Warner David S, Sheng Huaxin
Multidisciplinary Neuroprotection Laboratories, Center of Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
Department of Anesthesiology, The Fifth Central Hospital of Tianjin, Tianjin 300450, China.
Biology (Basel). 2022 Jun 24;11(7):957. doi: 10.3390/biology11070957.
Introduction Cardiac arrest (CA) and resuscitation induces global cerebral ischemia and reperfusion, causing neurologic deficits or death. Manganese porphyrins, superoxide dismutase mimics, are reportedly able to effectively reduce ischemic injury in brain, kidney, and other tissues. This study evaluates the efficacy of a third generation lipophilic Mn porphyrin, MnTnBuOE-2-PyP5+, Mn(III) ortho meso-tetrakis (N-n-butoxyethylpyridinium-2-yl)porphyrin (MnBuOE, BMX-001), in both mouse and rat models of CA. Methods Forty-eight animals were subjected to 8 min of CA and resuscitated subsequently by chest compression and epinephrine infusion. Vehicle or MnBuOE was given immediately after resuscitation followed by daily subcutaneous injections. Body weight, spontaneous activity, neurologic deficits, rotarod performance, and neuronal death were assessed. Kidney tubular injury was assessed in CA mice. Data were collected by the investigators who were blinded to the treatment groups. Results Vehicle mice had a mortality of 20%, which was reduced by 50% by MnBuOE. All CA mice had body weight loss, spontaneous activity decline, neurologic deficits, and decreased rotarod performance that were significantly improved at three days post MnBuOE daily treatment. MnBuOE treatment reduced cortical neuronal death and kidney tubular injury in mice (p < 0.05) but not hippocampus neuronal death (23% MnBuOE vs. 34% vehicle group, p = 0.49). In rats, they had a better body-weight recovery and increased rotarod latency after MnBuOE treatment when compared to vehicle group (p < 0.01 vs. vehicle). MnBuOE-treated rats had a low percentage of hippocampus neuronal death (39% MnBuOE vs. 49% vehicle group, p = 0.21) and less tubular injury (p < 0.05) relative to vehicle group. Conclusions We demonstrated the ability of MnBuOE to improve post-CA survival, as well as functional outcomes in both mice and rats, which jointly account for the improvement not only of brain function but also of the overall wellbeing of the animals. While MnBuOE bears therapeutic potential for treating CA patients, the females and the animals with comorbidities must be further evaluated before advancing toward clinical trials.
引言 心脏骤停（CA）及复苏会引发全脑缺血和再灌注，导致神经功能缺损或死亡。锰卟啉作为超氧化物歧化酶模拟物，据报道能够有效减轻脑、肾及其他组织的缺血性损伤。本研究评估了第三代亲脂性锰卟啉MnTnBuOE-2-PyP5+，即中-四（N-正丁氧基乙基吡啶鎓-2-基）锰（III）卟啉（MnBuOE，BMX-001）在小鼠和大鼠CA模型中的疗效。
方法 48只动物经历8分钟的心脏骤停，随后通过胸外按压和肾上腺素输注进行复苏。复苏后立即给予赋形剂或MnBuOE，随后每日皮下注射。评估体重、自发活动、神经功能缺损、转棒试验表现及神经元死亡情况。对CA小鼠的肾小管损伤进行评估。数据由对治疗组不知情的研究者收集。
结果 赋形剂处理的小鼠死亡率为20%，MnBuOE使其降低了50%。所有CA小鼠均出现体重减轻、自发活动减少、神经功能缺损及转棒试验表现下降，在每日给予MnBuOE治疗三天后均有显著改善。MnBuOE治疗减少了小鼠皮质神经元死亡和肾小管损伤（p<0.05），但未减少海马神经元死亡（MnBuOE组为23%，赋形剂组为34%，p=0.49）。在大鼠中，与赋形剂组相比，MnBuOE治疗后体重恢复更好，转棒试验潜伏期延长（与赋形剂组相比p<0.01）。与赋形剂组相比，MnBuOE处理的大鼠海马神经元死亡百分比低（MnBuOE组为39%，赋形剂组为49%，p=0.21），肾小管损伤也较少（p<0.05）。
结论 我们证明了MnBuOE能够提高心脏骤停后的存活率，并改善小鼠和大鼠的功能结局，这不仅改善了脑功能，也改善了动物的整体健康状况。虽然MnBuOE在治疗心脏骤停患者方面具有治疗潜力，但在推进至临床试验之前，必须对雌性动物和患有合并症的动物进行进一步评估。
