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Originally published by 2 Minute Medicine® (view original article). Reused on AccessPediatrics with permission.

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1. Following treatment with metformin, mouse models of Fragile X syndrome (FXS) demonstrated restored neurological signaling activity and synaptic function.

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2. Metformin administration reduced the behavioral and motor complications associated with FXS.

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Evidence Rating Level: 2 (Good)

Study Rundown:

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FXS is the most common genetic cause of autism spectrum disorders, resulting in social and behavioral deficits, as well as developmental delays and seizures. Due to a mutation in the gene that codes for fragile X mental retardation protein (FMRP), patients have excessive activation of various signaling pathways including the mechanistic target of rapamycin (mTOR) and extracellular signal–regulated kinase (ERK) pathways. Because metformin is known to play a role in inhibiting these pathways, this study assessed the efficacy of the drug for treating FXS.

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When mice lacking FMRP were treated with metformin, they showed a decrease of seizures and other motor and behavioral qualities associated with FXS. In the brains of these mice, structural and functional neurologic deficits were improved following treatment. To address metformin’s mechanism of action in improving FXS symptoms, researchers showed that there was decreased activation of the ERK pathway in certain areas of the brain in the treated mice.

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This study demonstrated that metformin, a drug commonly prescribed for diabetes, is a potential treatment for FXS. Because this drug has been tested previously, its safety profile is already known. Although the optimal dose and efficacy of this treatment in FXS patients need to be determined, metformin may be a new candidate therapy for this genetic disorder.

In-Depth [animal study]:

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Mice with a genetic deletion of FMRP were used as a model for FXS. When mice were administered 200 mg/kg of metformin daily for 10 days, they demonstrated decreased grooming activity (p< 0.01) and a decreased incidence of seizures. Staining of the dendrites in the treated mice revealed decreased density of dendritic spines to levels similar to wildtype mice (p<0.001), demonstrating the correction of structural neurological deficits. In addition to structural changes, the synaptic activity in pyramidal cells in the hippocampus was restored, with an increase in field excitatory postsynaptic potential slope (p< 0.01). In addition, one of the characteristic symptoms of FXS is enlarged testes, a trait that was improved through metformin treatment as seen by the reduction in testicular weight in treated mice (p<0.01).

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Next, the mechanism of action of this drug was evaluated. Brain tissue was isolated from treated mice and immunoblots were performed on various areas of the brain. ERK levels were decreased in the prefrontal cortex and hippocampus of the FXS mice treated with metformin, and phosphorylated ERK levels were decreased in the striatum (p<0.05). Although ERK signaling was not rescued in all brain areas, the improvement was sufficient to ameliorate symptoms attributed to FXS.

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