Abstract
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.
Highlights
Metformin is the most widely prescribed treatment for hyperglycemia and type 2 diabetes, even in pediatric patients [1,2]
We previously demonstrated that aberrant mitochondrial bioenergetics in the whole brain of Rett syndrome (RTT) mice is accompanied by alterations in the activity of mitochondrial respiratory-chain (MRC) II and V, in the absence of changes in the activity of MRC I, III and IV [19,20]
The present study evaluated the possibility to repurpose the anti-diabetic drug metformin for RTT, a severe neurologic disorder characterized by behavioral, physiological as well as metabolic alterations, for which no cure currently exists
Summary
Metformin is the most widely prescribed treatment for hyperglycemia and type 2 diabetes, even in pediatric patients [1,2]. Dyslipidaemia, fatty liver disease, insulin resistance and metabolic syndrome were uncovered [27,28], confirming that metabolic alterations in RTT patients and mouse models extend beyond mitochondria All these evidences suggest that MeCP2 plays an important role in the regulation of systemic metabolism and MECP2 mutations provide profound metabolic dysfunctions both at the peripheral and central levels [29]. Based on these evidences, the present study addressed whether metformin may rescue brain mitochondrial alterations and contrast the increased oxidative stress in a validated RTT mouse model bearing a MeCP2 truncating mutation (MeCP2-308 mice) [30,31]. By improving brain mitochondrial dysfunction, metformin may rescue the neurological phenotype, representing an innovative and repurposable therapeutic strategy for RTT
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