Department of Pediatrics, Medical University of South Carolina, Charleston, SC, United States.
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC, United States.
Brain Res. 2020 Aug 15;1741:146879. doi: 10.1016/j.brainres.2020.146879. Epub 2020 May 8.
The nitric oxide (NO) metabolome and the NO metabolite-based neurovascular protective pathways are dysregulated after stroke. The major NO metabolite S-nitrosoglutahione (GSNO) is essential for S-nitrosylation-based signaling events and the inhibition of S-nitrosoglutahione (GSNO)-metabolizing enzyme GSNO reductase (GSNOR) provides protective effects following cardiac ischemia. However, the role of GSNOR and GSNOR inhibition-mediated increased GSNO/S-nitrosylation is not understood in neurovascular diseases such as stroke. Because age is the major risk factor of stroke and recovery in aged stroke patients is low and slow, we investigated the efficacy of GSNOR inhibition using a GSNOR selective inhibitor N6022 in a clinically relevant middle-aged cerebral ischemia and reperfusion (IR) mouse model of stroke. N6022 (5 mg/kg; iv) treatment of IR mice at 2 h after reperfusion followed by the treatment of the same dose daily for 3 days reduced the infarct volume and decreased the neurological score. Daily treatment of IR animals with N6022 for 2 weeks significantly improved neurological score, brain infarctions/atrophy, survival rate, motor (measured by cylinder test) and cognitive (evaluated by novel object recognition test) functions which paralleled the decreased activity of GSNOR, reduced levels of peroxynitrite and decreased neurological score. These results are the first evidence of a new pathway for the treatment of stroke via the inhibition of GSNOR. Based on the efficacy of N6022 in the stroke animal model and its use in human therapeutic studies without toxicity, we submit that GSNOR is a druggable target, and N6022 is a promising drug candidate for human stroke therapy.
一氧化氮（NO）代谢物和基于 NO 代谢物的神经血管保护途径在中风后失调。主要的 NO 代谢物 S-亚硝基谷胱甘肽（GSNO）是基于 S-亚硝基化的信号事件所必需的，并且抑制 S-亚硝基谷胱甘肽（GSNO）-代谢酶 GSNO 还原酶（GSNOR）在心脏缺血后提供保护作用。然而，GSNOR 的作用和 GSNOR 抑制介导的增加的 GSNO/S-亚硝基化在神经血管疾病如中风中尚不清楚。由于年龄是中风的主要危险因素，并且老年中风患者的恢复速度较慢，因此我们使用一种选择性 GSNOR 抑制剂 N6022 在一种临床相关的中年脑缺血再灌注（IR）中风小鼠模型中研究了 GSNOR 抑制的疗效。IR 小鼠在再灌注后 2 小时给予 N6022（5mg/kg；iv）治疗，然后每天给予相同剂量治疗 3 天，可减少梗死体积并降低神经评分。IR 动物每天用 N6022 治疗 2 周可显著改善神经评分、脑梗死/萎缩、存活率、运动（通过圆筒试验测量）和认知（通过新物体识别试验评估）功能，这与 GSNOR 活性降低、过氧亚硝酸盐水平降低和神经评分降低相平行。这些结果是通过抑制 GSNOR 治疗中风的新途径的第一个证据。基于 N6022 在中风动物模型中的疗效及其在人类治疗研究中无毒性的使用，我们提出 GSNOR 是一个可成药的靶点，N6022 是人类中风治疗的有前途的候选药物。
