PDF(Pubmed)
Abstract：
Neonatal hypoxia-ischemia (HI) affects 2-3 per 1000 live births in developed countries and up to 26 per 1000 live births in developing countries. It is estimated that of the 750,000 infants experiencing a hypoxic-ischemic event during birth per year, more than 400,000 will be severely affected. As treatment options are limited, rapidly identifying new therapeutic avenues is critical, and repurposing drugs already in clinical use offers a fast-track route to clinic. One emerging avenue for therapeutic intervention in neonatal HI is to target mitochondrial dysfunction, which occurs early in the development of brain injury. Mitochondrial dynamics are particularly affected, with mitochondrial fragmentation occurring at the expense of the pro-fusion protein Optic Atrophy (OPA)1. OPA1, together with mitofusins (MFN)1/2, are required for membrane fusion, and therefore, protecting their function may also safeguard mitochondrial dynamics. Leflunomide, an FDA-approved immunosuppressant, was recently identified as an activator of MFN2 with partial effects on OPA1 expression. We, therefore, treated C17.2 cells with Leflunomide before or after oxygen-glucose deprivation, an in vitro mimic of HI, to determine its efficacy as a neuroprotection and inhibitor of mitochondrial dysfunction. Leflunomide increased baseline OPA1 but not MFN2 expression in C17.2 cells. However, Leflunomide was unable to promote cell survival following OGD. Equally, there was no obvious effect on mitochondrial morphology or bioenergetics. These data align with studies suggesting that the tissue and mitochondrial protein profile of the target cell/tissue are critical for taking advantage of the therapeutic actions of Leflunomide.
摘要：
新生儿缺氧缺血（HI）在发达国家影响每1000个活产2-3个，在发展中国家影响每1000个活产26个。据估计，每年有750,000名婴儿在出生时经历缺氧缺血事件，超过40万人将受到严重影响。由于治疗选择有限，快速确定新的治疗途径至关重要，重新利用已经在临床使用的药物为临床提供了一条快速的途径。新生儿HI治疗干预的一个新兴途径是针对线粒体功能障碍，发生在脑损伤发展的早期。线粒体动力学尤其受到影响，线粒体片段化以牺牲前融合蛋白视神经萎缩（OPA）1为代价。膜融合需要OPA1和线粒体融合蛋白（MFN）1/2，因此,保护它们的功能也可能保护线粒体动力学。来氟米特,FDA批准的免疫抑制剂,最近被鉴定为MFN2的激活剂，对OPA1表达有部分影响。我们,因此,在氧-葡萄糖剥夺之前或之后用来氟米特处理C17.2细胞，HI的体外模拟物，以确定其作为线粒体功能障碍的神经保护和抑制剂的功效。来氟米特增加C17.2细胞中的基线OPA1但不增加MFN2表达。然而,来氟米特不能促进OGD后的细胞存活。同样,对线粒体形态和生物能学无明显影响。这些数据与表明靶细胞/组织的组织和线粒体蛋白质谱对于利用来氟米特的治疗作用至关重要的研究一致。
