Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
Department NEUROFARBA, Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.
Br J Pharmacol. 2018 Jan;175(2):272-283. doi: 10.1111/bph.13790. Epub 2017 May 12.
Dexpramipexole, a drug recently tested in patients with amyotrophic lateral sclerosis (ALS,) is able to bind F1Fo ATP synthase and increase mitochondrial ATP production. Here, we have investigated its effects on experimental ischaemic brain injury.
The effects of dexpramipexole on bioenergetics, Ca fluxes, electrophysiological functions and death were evaluated in primary neural cultures and hippocampal slices exposed to oxygen-glucose deprivation (OGD). Effects on infarct volumes and neurological functions were also evaluated in mice following proximal or distal middle cerebral artery occlusion (MCAo). Distribution of dexpramipexole within the ischaemic brain was evaluated by means of mass spectrometry imaging.
Dexpramipexole increased mitochondrial ATP production in cultured neurons or glia and reduces energy failure, prevents intracellular Ca overload and affords cytoprotection when cultures are exposed to OGD. This compound also counteracted ATP depletion, mitochondrial swelling, anoxic depolarization, loss of synaptic activity and neuronal death in hippocampal slices subjected to OGD. Post-ischaemic treatment with dexpramipexole, at doses consistent with those already used in ALS patients, reduced brain infarct size and ameliorated neuroscore in mice subjected to transient or permanent MCAo. Notably, the concentrations of dexpramipexole reached within the ischaemic penumbra equalled those found neuroprotective in vitro.
Dexpramipexole, a compound able to increase mitochondrial F1Fo ATP-synthase activity reduced ischaemic brain injury. These findings, together with the excellent brain penetration and favourable safety profile in humans, make dexpramipexole a drug with realistic translational potential for the treatment of stroke.
This article is part of a themed section on Inventing New Therapies Without Reinventing the Wheel: The Power of Drug Repurposing. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.
德普拉米克斯ole（dexpramipexole）是一种最近在肌萎缩侧索硬化症（ALS）患者中进行测试的药物，能够与 F1Fo ATP 合酶结合并增加线粒体 ATP 的产生。在这里，我们研究了它对实验性脑缺血损伤的影响。
在原代神经培养物和海马切片中，评估德普拉米克斯ole 对氧葡萄糖剥夺（OGD）暴露后的生物能学、Ca 流、电生理功能和死亡的影响。还在近端或远端大脑中动脉闭塞（MCAo）后评估德普拉米克斯ole 对小鼠梗死体积和神经功能的影响。通过质谱成像评估德普拉米克斯ole 在缺血性大脑中的分布。
德普拉米克斯ole 增加了培养神经元或神经胶质中的线粒体 ATP 产生，并减少了能量衰竭，防止了细胞内 Ca 超载，并在培养物暴露于 OGD 时提供了细胞保护。当在缺氧的情况下，这种化合物还对抗了 ATP 耗竭、线粒体肿胀、缺氧性去极化、突触活动丧失和神经元死亡。在接受短暂或永久性 MCAo 的小鼠中，给予德普拉米克斯ole 进行缺血后治疗，剂量与已在 ALS 患者中使用的剂量一致，可减少脑梗死面积并改善神经评分。值得注意的是，在缺血半影区内达到的德普拉米克斯ole 浓度与体外发现的神经保护作用相当。
能够增加线粒体 F1Fo ATP 合酶活性的德普拉米克斯ole 减少了缺血性脑损伤。这些发现，加上在人类中良好的脑穿透性和有利的安全性概况，使德普拉米克斯ole 成为一种具有现实转化潜力的治疗中风的药物。
本文是专题“发明新疗法而不重新发明轮子：药物再利用的力量”的一部分。要查看本节中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.2/issuetoc.html。
