Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Florence, Italy.
Centre of Immunological Research DENOTHE, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Br J Pharmacol. 2020 Jul;177(14):3342-3356. doi: 10.1111/bph.15058. Epub 2020 Apr 18.
Drugs able to counteract progressive multiple sclerosis (MS) represent a largely unmet therapeutic need. Even though the pathogenesis of disease evolution is still obscure, accumulating evidence indicates that mitochondrial dysfunction plays a causative role in neurodegeneration and axonopathy in progressive MS patients. Here, we investigated the effects of dexpramipexole, a compound with a good safety profile in humans and able to sustain mitochondria functioning and energy production, in a mouse model of progressive MS.
Female non-obese diabetic mice were immunized with MOG . Functional, immune and neuropathological parameters were analysed during disease evolution in animals treated or not with dexpramipexole. The compound's effects on bioenergetics and neuroprotection were also evaluated in vitro.
We found that oral treatment with dexpramipexole at a dose consistent with that well tolerated in humans delayed disability progression, extended survival, counteracted reduction of spinal cord mitochondrial DNA content and reduced spinal cord axonal loss of mice. Accordingly, the drug sustained in vitro bioenergetics of mouse optic nerve and dorsal root ganglia and counteracted neurodegeneration of organotypic mouse cortical cultures exposed to the adenosine triphosphate-depleting agents oligomycin or veratridine. Dexpramipexole, however, was unable to affect the adaptive and innate immune responses both in vivo and in vitro.
The present findings corroborate the hypothesis that neuroprotective agents may be of relevance to counteract MS progression and disclose the translational potential of dexpramipexole to treatment of progressive MS patients as a stand-alone or adjunctive therapy.
能够对抗进行性多发性硬化症（MS）的药物代表了一种极大的未满足的治疗需求。尽管疾病进展的发病机制仍不清楚，但越来越多的证据表明，线粒体功能障碍在进行性 MS 患者的神经退行性变和轴突病中起因果作用。在这里，我们研究了 dexpramipexole 在进行性 MS 小鼠模型中的作用，dexpramipexole 是一种在人类中具有良好安全性的化合物，能够维持线粒体功能和能量产生。
雌性非肥胖型糖尿病小鼠用 MOG 免疫。在未用 dexpramipexole 或用 dexpramipexole 治疗的动物中，分析了疾病进展过程中的功能、免疫和神经病理学参数。还评估了该化合物对生物能学和神经保护的影响。
我们发现，以与人类耐受良好的剂量口服给予 dexpramipexole 可延迟残疾进展、延长生存期、对抗脊髓线粒体 DNA 含量减少和减少小鼠脊髓轴突丢失。因此，该药物维持了体外培养的小鼠视神经和背根神经节的生物能学，并对抗暴露于三磷酸腺苷耗竭剂寡霉素或藜芦碱的器官型小鼠皮质培养物中的神经退行性变。然而，dexpramipexole 既不能影响体内和体外的适应性和先天免疫反应。
本研究结果支持了神经保护剂可能对抗 MS 进展具有相关性的假设，并揭示了 dexpramipexole 作为一种独立或辅助治疗用于治疗进行性 MS 患者的转化潜力。
