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

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.

Abnormalities of synaptic mitochondria in autism spectrum disorder and related neurodevelopmental disorders

“…The treatment with free radical scavengers like Trolox—a derivative from vitamin E—rescued mitochondrial functionality and restored synaptic LTP in the hippocampus and hippocampal astrocytes of this RS mouse model [ 131 , 132 ]. Other compounds such as metformin and quercetin rescued the mitochondrial phenotype in whole brains of Mecp2-308 mutant mice and primary astrocytic cultures, respectively [ 133 , 134 ]. The downregulation of Mecp2 in microglia generates increased oxygen consumption, less ATP production, and overexpression of Snat1—a glutamine transporter encoded by Slc38a1 , a Mecp2 target gene previously identified in a ChIP-seq assay [ 135 ].…”

“…al 2019 [ 144 ] Increased ROS, intensified oxygen consumption Mecp2 -KO mice Hippocampus, cortex Zuliani et. al 2020 [ 133 ] Reduced ATP production, reduced activities of mitochondrial complexes II and V, decreased protein expression of ETC complexes, increased oxidative stress Mecp2-308 mice Whole brain Dave et. al 2020 [ 134 ] Reduced activities of ETC complexes, reduced Ψ m Mecp2 -KO astrocytes Primary cultured astrocytes Ebrahimi-Fakhari et.…”

Treatment with the Bacterial Toxin CNF1 Selectively Rescues Cognitive and Brain Mitochondrial Deficits in a Female Mouse Model of Rett Syndrome Carrying a MeCP2-Null Mutation

“…Importantly, this was accompanied by restoration of mitochondrial complex activities, suggesting that the rescue of the brain energy reservoir may be fundamental to improve cognitive function in RTT. Indeed, maintaining a steady balance between nutrient supply and energy demand is an essential mechanism for preserving higher brain functions under different conditions [39][40][41].…”

The Molecular Functions of MeCP2 in Rett Syndrome Pathology

“…Another promising area for potential Rett therapies, is the repurposing of existing FDA approved compounds. For example, in 2020, it was found that the diabetes drug, metformin, reduces mitochondrial defects and damage from oxidative stress in Mecp2 308 −/+ truncation female mice (Zuliani et al, 2020). Finally, a recently developed compound for Alzheimer's disease reduced motor defects, learning deficits and breathing abnormalities in Mecp2 −/+ female mice with minimal side effects (Kaufmann et al, 2019).…”