Department of Pharmaceutical Sciences, School of Pharmacy, West Virginia University, 1 Medical Center Drive, Morgantown, West Virginia, 26506, USA.
Department of Neurology, College of Medicine, University of Oklahoma HSC, Oklahoma City, Oklahoma, USA.
Pharm Res. 2021 May;38(5):803-817. doi: 10.1007/s11095-021-03046-4. Epub 2021 May 12.
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.
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.
NL-1 decreased hydrogen peroxide production with an IC 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%.
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.
由于脑缺血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。由于氧化应激是中风后导致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点可以防止脑缺血后的再灌注损伤，这里的重点是一种调节细胞生物能量的线粒体蛋白，mitoNEET。
在这项研究中，我们评估了 mitoNEET 配体 NL-1 的药理学，并在 C57Bl/6 缺血性中风小鼠模型中评估了 NL-1 在体内治疗中的作用。
NL-1 以 5.95 μM 的 IC 在神经元细胞（N2A）中降低了过氧化氢的产生。NL-1 的体内活性在 1 小时短暂性大脑中动脉闭塞（t-MCAO）缺血性中风小鼠模型中进行了评估。我们发现，在再灌注时用 NL-1（10 mg/kg，ip）治疗并允许恢复 24 小时的小鼠，与假损伤小鼠相比，梗死体积减少了 43%，水肿减少了 68%。此外，我们发现当 NL-1 在 t-MCAO 后 15 分钟给药时，缺血体积减少了 41%，中风相关的水肿减少了 63%。
作为我们假设的支持，正如预期的那样，NL-1 未能减少永久性光血栓闭塞性中风模型中的中风梗死。本报告证明了使用 mitoNEET 配体（如 NL-1）作为治疗脑中风再灌注损伤的新型线粒体药物的潜在治疗益处。
