Zuliani Ilaria, Urbinati Chiara, Valenti Daniela, Quattrini Maria Cristina, Medici Vanessa, Cosentino Livia, Pietraforte Donatella, Di Domenico Fabio, Perluigi Marzia, Vacca Rosa Anna, De Filippis Bianca
Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy.
Center for Behavioral Sciences and Mental Health, Istituto Superiore di Sanità, 00161 Rome, Italy.
J Clin Med. 2020 Jun 1;9(6):1669. doi: 10.3390/jcm9061669.
Metformin is the first-line therapy for diabetes, even in children, and a promising attractive candidate for drug repurposing. Mitochondria are emerging as crucial targets of metformin action both in the periphery and in the brain. The present study evaluated whether treatment with metformin may rescue brain mitochondrial alterations and contrast the increased oxidative stress in a validated mouse model of Rett syndrome (RTT), a rare neurologic disorder of monogenic origin characterized by severe behavioral and physiological symptoms. No cure for RTT is available. In fully symptomatic RTT mice (12 months old MeCP2-308 heterozygous female mice), systemic treatment with metformin (100 mg/kg ip for 10 days) normalized the reduced mitochondrial ATP production and ATP levels in the whole-brain, reduced brain oxidative damage, and rescued the increased production of reactive oxidizing species in blood. A 10-day long treatment with metformin also boosted pathways related to mitochondrial biogenesis and antioxidant defense in the brain of metformin-treated RTT mice. This treatment regimen did not improve general health status and motor dysfunction in RTT mice at an advanced stage of the disease. Present results provide evidence that systemic treatment with metformin may represent a novel, repurposable therapeutic strategy for RTT.
二甲双胍是糖尿病的一线治疗药物，即使对儿童也是如此，并且是药物重新利用的一个有前景的有吸引力的候选药物。线粒体正在成为二甲双胍在外周和大脑中作用的关键靶点。本研究评估了在一种经过验证的雷特综合征（RTT）小鼠模型中，二甲双胍治疗是否可以挽救脑线粒体改变并对抗氧化应激增加，RTT是一种罕见的单基因起源的神经疾病，其特征为严重的行为和生理症状。目前尚无治愈RTT的方法。在完全出现症状的RTT小鼠（12月龄MeCP2-308杂合雌性小鼠）中，二甲双胍全身治疗（100mg/kg腹腔注射，持续10天）使全脑线粒体ATP生成减少和ATP水平恢复正常，减轻了脑氧化损伤，并挽救了血液中活性氧化物质生成的增加。对接受二甲双胍治疗的RTT小鼠进行为期10天的二甲双胍治疗，也增强了与线粒体生物发生和抗氧化防御相关的通路。这种治疗方案在疾病晚期并未改善RTT小鼠的总体健康状况和运动功能障碍。目前的结果提供了证据，表明二甲双胍全身治疗可能代表一种针对RTT的新型、可重新利用的治疗策略。
