The Anti-Diabetic Drug Metformin Rescues Aberrant Mitochondrial Activity and Restrains Oxidative Stress in a Female Mouse Model of Rett Syndrome

被引:20
作者
Zuliani, Ilaria [1 ]
Urbinati, Chiara [2 ]
Valenti, Daniela [3 ]
Quattrini, Maria Cristina [4 ]
Medici, Vanessa [2 ]
Cosentino, Livia [2 ]
Pietraforte, Donatella [4 ]
Di Domenico, Fabio [1 ]
Perluigi, Marzia [1 ]
Vacca, Rosa Anna [3 ]
De Filippis, Bianca [2 ]
机构
[1] Sapienza Univ Rome, Dept Biochem Sci, I-00185 Rome, Italy
[2] Ist Super Sanita, Ctr Behav Sci & Mental Hlth, I-00161 Rome, Italy
[3] CNR, Inst Biomembranes Bioenerget & Mol Biotechnol, I-70126 Bari, Italy
[4] Ist Super Sanita, Core Facil, I-00161 Rome, Italy
关键词
Rett syndrome; metformin; repurposing; PGC-1; alpha; Nrf2; SEROTONIN RECEPTOR 7; DOWN-SYNDROME; REPURPOSING METFORMIN; TRANSCRIPTION FACTOR; SKELETAL-MUSCLE; FRAGILE-X; DYSFUNCTION; BRAIN; MECP2; IMPAIRMENT;
D O I
10.3390/jcm9061669
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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页数:19
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