靶向 GSNOR 用于中年小鼠中风模型的功能恢复。,Brain Research

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靶向 GSNOR 用于中年小鼠中风模型的功能恢复。
Brain Research ( IF 2.7 ) Pub Date : 2020-05-08 , DOI: 10.1016/j.brainres.2020.146879
Mushfiquddin Khan ₁ , Pavan Kumar ₁ , Fei Qiao ₂ , S M Touhidul Islam ₁ , Avtar K Singh ₃ , Je-Seong Won ₂ , Wayne Feng ₄ , Inderjit Singh ₅

Affiliation

中风后，一氧化氮 (NO) 代谢组和基于 NO 代谢物的神经血管保护通路失调。NO 的主要代谢物 S-亚硝基谷胱甘肽 (GSNO) 对基于 S-亚硝基化的信号事件至关重要，S-亚硝基谷胱甘肽 (GSNO) 代谢酶 GSNO 还原酶 (GSNOR) 的抑制可在心脏缺血后提供保护作用。然而，在神经血管疾病如中风中，GSNOR 和 GSNOR 抑制介导的 GSNO/S-亚硝基化增加的作用尚不清楚。由于年龄是卒中的主要危险因素，老年卒中患者的恢复缓慢且缓慢，因此我们在临床相关的中年脑缺血再灌注 (IR) 小鼠模型中研究了使用 GSNOR 选择性抑制剂 N6022 抑制 GSNOR 的功效。中风。N6022（5 毫克/公斤；iv) 在再灌注后 2 小时处理 IR 小鼠，然后每天以相同剂量处理 3 天，可减少梗塞体积并降低神经系统评分。用 N6022 每日治疗 IR 动物 2 周显着改善神经系统评分、脑梗塞/萎缩、存活率、运动（通过圆柱体测试测量）和认知（通过新物体识别测试评估）功能，这与 GSNOR 活性降低平行，减少过氧亚硝酸盐水平和神经系统评分降低。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功效及其在无毒性的人类治疗研究中的应用，我们认为 GSNOR 是一种可药物靶点，

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Targeting GSNOR for functional recovery in a middle-aged mouse model of stroke.

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.

更新日期：2020-05-08

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