Li Xuan, Duan Weina, Du Li, Chu Dongmei, Wang Peng, Yang Zhong, Qu Xingguang, Yang Zhenxing, Batinic-Haberle Ines, Spasojevic Ivan, Warner David S, Crapo James D, Treggiari Miriam M, Sheng Huaxin
Multidisciplinary Neuroprotection Laboratories, Center of Perioperative Organ Protection, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710, USA.
Department of Neurosurgery, Duke University Medical Center, Durham, NC 27710, USA.
Antioxidants (Basel). 2023 Oct 13;12(10):1861. doi: 10.3390/antiox12101861.
Endovascular mechanical thrombectomy, combined with a tissue plasminogen activator (t-PA), is efficacious as a standard care for qualifying ischemic stroke patients. However, > 50% of thrombectomy patients still have poor outcomes. Manganese porphyrins, commonly known as mimics of superoxide dismutases, are potent redox-active catalytic compounds that decrease oxidative/nitrosative stress and in turn decrease inflammatory responses, mitigating therefore the secondary injury of the ischemic brain. This study investigates the effect of intracarotid MnTnBuOE-2-PyP (BMX-001) administration on long-term, 28-day post-stroke recovery in a clinically relevant setting. The 90 min of transient middle cerebral artery occlusion was performed in young, aged, male, female, and spontaneous hypertension rats. All physiological parameters, including blood pressure, blood gas, glucose, and temperature, were well controlled during ischemia. Either BMX-001 or a vehicle solution was infused through the carotid artery immediately after the removal of filament, mimicking endovascular thrombectomy, and was followed by 7 days of subcutaneous injection. Neurologic deficits and infarct volume were assessed at 28 days in a blinded manner. The effects of BMX-001 on the carotid arterial wall and blood-brain barrier permeability and its interaction with t-PA were assessed in normal rats. There were no intra-group differences in physiological variables. BMX-001-treated stroke rats regained body weight earlier, performed better in behavioral tests, and had smaller brain infarct size compared to the vehicle-treated group. No vascular wall damage and blood-brain barrier permeability changes were detected after the BMX-001 infusion. There was no drug interaction between BMX-001 and t-PA. Intracarotid BMX-001 infusion was safe, and it significantly improved stroke outcomes in rats. These findings indicate that BMX-001 is a candidate drug as an adjunct treatment for thrombectomy procedure to further improve the neurologic outcomes of thrombectomy patients. This study warrants further clinical investigation of BMX-001 as a new stroke therapy.
血管内机械取栓术联合组织型纤溶酶原激活剂（t-PA），作为符合条件的缺血性中风患者的标准治疗方法是有效的。然而，超过50%的取栓术患者仍然预后不良。锰卟啉，通常被称为超氧化物歧化酶模拟物，是一种强大的氧化还原活性催化化合物，可降低氧化/亚硝化应激，进而减少炎症反应，从而减轻缺血性脑的继发性损伤。本研究在临床相关环境中，研究颈动脉内注射MnTnBuOE-2-PyP（BMX-001）对中风后28天长期恢复的影响。对年轻、老年、雄性、雌性和自发性高血压大鼠进行90分钟的大脑中动脉短暂闭塞。在缺血期间，所有生理参数，包括血压、血气、血糖和体温，均得到良好控制。在移除细丝后，立即通过颈动脉注入BMX-001或赋形剂溶液，模拟血管内取栓术，随后进行7天的皮下注射。在28天时以盲法评估神经功能缺损和梗死体积。在正常大鼠中评估BMX-001对颈动脉壁和血脑屏障通透性的影响及其与t-PA的相互作用。生理变量在组内无差异。与赋形剂治疗组相比，BMX-001治疗的中风大鼠体重恢复更早，行为测试表现更好，脑梗死面积更小。注入BMX-001后未检测到血管壁损伤和血脑屏障通透性变化。BMX-001与t-PA之间没有药物相互作用。颈动脉内注入BMX-001是安全的，并且它显著改善了大鼠的中风预后。这些发现表明，BMX-001作为取栓术的辅助治疗药物，有望进一步改善取栓术患者的神经功能预后。本研究值得对BMX-001作为一种新的中风治疗方法进行进一步的临床研究。
