Zaidi Syed Kashif, Hoda Md Nasrul, Tabrez Shams, Khan Mohammad Imran
Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA.
Antioxidants (Basel). 2022 Oct 18;11(10):2051. doi: 10.3390/antiox11102051.
The restoration of cerebral blood flow (CBF) to achieve brain tissue oxygenation (PbtO) is the primary treatment for ischemic stroke, a significant cause of adult mortality and disability worldwide. Nitric oxide (NO) and its bioactive -nitrosylated (SNO) reservoirs, such as -nitrosoglutathione (GSNO), induce hypoxic vasodilation to enhance CBF during ischemia. The endogenous pool of SNOs/GSNO is enhanced via the activation of endothelial NO synthase (eNOS/NOS3) and by the suppression of class III alcohol dehydrogenase 5 (ADH5), also known as GSNO reductase (GSNOR). Remote ischemic conditioning (RIC), which augments NOS3 activity and SNO, is an emerging therapy in acute stroke. However, RIC has so far shown neutral effects in stroke clinical trials. As the majority of stroke patients are presented with endothelial dysfunctions and comorbidities, we tested the hypothesis that NOS3 dysfunction and diabetes will abolish the protective effects of RIC therapy in stroke, and the prior inhibition of GSNOR will turn RIC protective. Our data demonstrate that RIC during thrombotic stroke failed to enhance the CBF and the benefits of thrombolysis in NOS3 mutant (NOS3) mice, a genetic model of NOS3 dysfunction. Interestingly, thrombotic stroke in diabetic mice enhanced the activity of GSNOR as early as 3 h post-stroke without decreasing the plasma nitrite (NO). In thrombotic stroke, neither a pharmacological inhibitor of GSNOR (GRI) nor RIC therapy alone was protective in diabetic mice. However, prior treatment with GRI followed by RIC enhanced the CBF and improved recovery. In a reperfused stroke model, the GRI-RIC combination therapy in diabetic mice augmented PbtO, a translatory signature of successful microvascular reflow. In addition, RIC therapy unexpectedly increased the inflammatory markers at 6 h post-stroke in diabetic stroke that were downregulated in combination with GRI while improving the outcomes. Thus, we conclude that preexisting NOS3 dysfunctions due to comorbidities may neutralize the benefits of RIC in stroke, which can be turned protective in combination with GRI. Our findings may support the future clinical trial of RIC in comorbid stroke. Further studies are warranted to test and develop SNO reservoirs as the blood-associated biomarker to monitor the response and efficacy of RIC therapy in stroke.
恢复脑血流量（CBF）以实现脑组织氧合（PbtO）是缺血性中风的主要治疗方法，缺血性中风是全球成人死亡和残疾的重要原因。一氧化氮（NO）及其生物活性亚硝基化（SNO）储备，如亚硝基谷胱甘肽（GSNO），在缺血期间诱导缺氧性血管舒张以增强CBF。通过激活内皮型一氧化氮合酶（eNOS/NOS3）和抑制Ⅲ类乙醇脱氢酶5（ADH5，也称为GSNO还原酶（GSNOR））来增强SNO/GSNO的内源性储备。远程缺血预处理（RIC）可增强NOS3活性和SNO，是急性中风中一种新兴的治疗方法。然而，RIC在中风临床试验中迄今显示出中性效果。由于大多数中风患者存在内皮功能障碍和合并症，我们测试了以下假设：NOS3功能障碍和糖尿病将消除RIC疗法对中风的保护作用，而预先抑制GSNOR将使RIC具有保护作用。我们的数据表明，在血栓性中风期间，RIC未能增强NOS3突变体（NOS3）小鼠（NOS3功能障碍的遗传模型）的CBF以及溶栓的益处。有趣的是，糖尿病小鼠的血栓性中风早在中风后3小时就增强了GSNOR的活性，而血浆亚硝酸盐（NO）并未降低。在血栓性中风中，GSNOR的药理抑制剂（GRI）和RIC疗法单独使用对糖尿病小鼠均无保护作用。然而，先用GRI治疗再进行RIC可增强CBF并改善恢复情况。在再灌注中风模型中，糖尿病小鼠的GRI-RIC联合疗法可增加PbtO，这是成功微血管再灌注的一个转化指标。此外，RIC疗法意外地增加了糖尿病中风后6小时的炎症标志物，而与GRI联合使用时这些标志物会下调，同时改善了预后。因此，我们得出结论，合并症导致的预先存在的NOS3功能障碍可能会抵消RIC对中风的益处，而与GRI联合使用时可使其具有保护作用。我们的发现可能支持未来对合并症中风患者进行RIC的临床试验。有必要进行进一步研究，以测试和开发SNO储备作为与血液相关的生物标志物，以监测RIC疗法对中风的反应和疗效。
