Purpose

Therapeutic strategies to treat ischemic stroke are limited due to the heterogeneity of cerebral ischemic injury and the mechanisms that contribute to the cell death. Since oxidative stress is one of the primary mechanisms that cause brain injury post-stroke, we hypothesized that therapeutic targets that modulate mitochondrial function could protect against reperfusion-injury after cerebral ischemia, with the focus here on a mitochondrial protein, mitoNEET, that modulates cellular bioenergetics.

Method

In this study, we evaluated the pharmacology of the mitoNEET ligand NL-1 in an in vivo therapeutic role for NL-1 in a C57Bl/6 murine model of ischemic stroke.

Results

NL-1 decreased hydrogen peroxide production with an IC₅₀ of 5.95 μM in neuronal cells (N2A). The in vivo activity of NL-1 was evaluated in a murine 1 h transient middle cerebral artery occlusion (t-MCAO) model of ischemic stroke. We found that mice treated with NL-1 (10 mg/kg, i.p.) at time of reperfusion and allowed to recover for 24 h showed a 43% reduction in infarct volume and 68% reduction in edema compared to sham-injured mice. Additionally, we found that when NL-1 was administered 15 min post-t-MCAO, the ischemia volume was reduced by 41%, and stroke-associated edema by 63%.

Conclusion

As support of our hypothesis, as expected, NL-1 failed to reduce stroke infarct in a permanent photothrombotic occlusion model of stroke. This report demonstrates the potential therapeutic benefits of using mitoNEET ligands like NL-1 as novel mitoceuticals for treating reperfusion-injury with cerebral stroke.

中文翻译：

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线粒体 mitoNEET 配体 NL-1 在短暂性脑缺血性中风的小鼠模型中具有保护作用

 目的

由于脑缺血性损伤的异质性和导致细胞死亡的机制，治疗缺血性中风的治疗策略受到限制。由于氧化应激是导致中风后脑损伤的主要机制之一，我们假设调节线粒体功能的治疗靶标可以防止脑缺血后的再灌注损伤，重点关注线粒体蛋白 mitoNEET，它调节细胞生物能量学。

 方法

在本研究中，我们评估了 mitoNEET 配体 NL-1 在缺血性中风 C57Bl/6 小鼠模型中 NL-1 体内治疗作用的药理学。

 结果

NL-1 降低神经元细胞 (N2A) 中过氧化氢的产生，IC ₅₀为 5.95 μM。在小鼠缺血性中风 1 小时短暂大脑中动脉闭塞 (t-MCAO) 模型中评估 NL-1 的体内活性。我们发现，与假损伤小鼠相比，再灌注时接受 NL-1（10 mg/kg，腹腔注射）治疗并允许恢复 24 小时的小鼠表现出梗塞体积减少 43%，水肿减少 68%。此外，我们发现，当 t-MCAO 后 15 分钟给予 NL-1 时，缺血体积减少了 41%，中风相关水肿减少了 63%。

 结论

作为我们假设的支持，正如预期的那样，NL-1 未能在中风的永久性光血栓闭塞模型中减少中风梗塞。该报告证明了使用 NL-1 等 mitoNEET 配体作为新型线粒体药物治疗脑中风再灌注损伤的潜在治疗益处。