The safety and efficacy of metformin in fragile X syndrome: An open-label study

Proteau-Lemieux, Mélodie; Lacroix, Angélina; Galarneau, Luc; Corbin, François; Lepage, Jean‐François; Çaku, Artuela

doi:10.1016/j.pnpbp.2021.110307

Cited by 21 publications

(13 citation statements)

References 39 publications

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“…Both overactivation of metabotropic glutamate receptors (mGluRs) leading to increased neuronal excitability (5,6), as well as a compromised GABAergic system resulting in reduced inhibition (7), have been discussed as potential contributors to excitation/inhibition imbalance in FXS. Hence, the neurophysiological abnormalities found in humans support these notions of excitation/inhibition imbalance, including enhanced electrocortical responses and reduced intracortical inhibition, as measured by transcranial magnetic stimulation (8,9). In addition, reduced levels of cAMP in FXS further interfere with neuronal connectivity and inhibitory responses (10).…”

Section: Introductionmentioning

confidence: 80%

EEG Signal Complexity Is Reduced During Resting-State in Fragile X Syndrome

et al. 2021

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Introduction: Fragile X syndrome (FXS) is a genetic disorder caused by a mutation of the fragile X mental retardation 1 gene (FMR1). FXS is associated with neurophysiological abnormalities, including cortical hyperexcitability. Alterations in electroencephalogram (EEG) resting-state power spectral density (PSD) are well-defined in FXS and were found to be linked to neurodevelopmental delays. Whether non-linear dynamics of the brain signal are also altered remains to be studied.Methods: In this study, resting-state EEG power, including alpha peak frequency (APF) and theta/beta ratio (TBR), as well as signal complexity using multi-scale entropy (MSE) were compared between 26 FXS participants (ages 5–28 years), and 7 neurotypical (NT) controls with a similar age distribution. Subsequently a replication study was carried out, comparing our cohort to 19 FXS participants independently recorded at a different site.Results: PSD results confirmed the increased gamma, decreased alpha power and APF in FXS participants compared to NT controls. No alterations in TBR were found. Importantly, results revealed reduced signal complexity in FXS participants, specifically in higher scales, suggesting that altered signal complexity is sensitive to brain alterations in this population. The replication study mostly confirmed these results and suggested critical points of stagnation in the neurodevelopmental curve of FXS.Conclusion: Signal complexity is a powerful feature that can be added to the electrophysiological biomarkers of brain maturation in FXS.

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Section: Introductionmentioning

confidence: 80%

EEG Signal Complexity Is Reduced During Resting-State in Fragile X Syndrome

et al. 2021

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“…The Transcranial Magnetic Stimulation parameters showed an increase in corticospinal inhibition mediated by GABA A and GABA B mechanisms. This study demonstrated the safety of metformin in normoglycemic patients with FXS, and suggested the potential of this medication in modifying GABA-mediated inhibition, a hallmark of FXS pathophysiology [154].…”

Section: Metforminmentioning

confidence: 60%

Fragile X Syndrome: From Molecular Aspect to Clinical Treatment

Protić

Aishworiya

Salcedo-Arellano

et al. 2022

IJMS

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Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the full mutation as well as highly localized methylation of the fragile X mental retardation 1 (FMR1) gene on the long arm of the X chromosome. Children with FXS are commonly co-diagnosed with Autism Spectrum Disorder, attention and learning problems, anxiety, aggressive behavior and sleep disorder, and early interventions have improved many behavior symptoms associated with FXS. In this review, we performed a literature search of original and review articles data of clinical trials and book chapters using MEDLINE (1990–2021) and ClinicalTrials.gov. While we have reviewed the biological importance of the fragile X mental retardation protein (FMRP), the FXS phenotype, and current diagnosis techniques, the emphasis of this review is on clinical interventions. Early non-pharmacological interventions in combination with pharmacotherapy and targeted treatments aiming to reverse dysregulated brain pathways are the mainstream of treatment in FXS. Overall, early diagnosis and interventions are fundamental to achieve optimal clinical outcomes in FXS.

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“…In a rat model of diabetic epilepsy, metformin corrected the abnormal level of glutamate and GABA values in the hippocampus [ 171 ]. In an open-label study, increased corticospinal inhibition mediated by the GABA A and GABA B mechanisms was observed by transcranial magnetic stimulation in 15 FXS patients with metformin treatment, suggesting the potential of metformin in modifying GABA-mediated inhibition [ 172 ]. Glutamate excitatory toxicity in nutrient-deficient cells was mitigated after metformin treatment, mediated partly by downregulation of AMPK and subsequent reduction in autophagy [ 173 ].…”

Section: Potential Mechanisms For Actions Of Metformin In the Brainmentioning

confidence: 99%

Actions of Metformin in the Brain: A New Perspective of Metformin Treatments in Related Neurological Disorders

Zhou

Fei

2022

IJMS

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Metformin is a first-line drug for treating type 2 diabetes mellitus (T2DM) and one of the most commonly prescribed drugs in the world. Besides its hypoglycemic effects, metformin also can improve cognitive or mood functions in some T2DM patients; moreover, it has been reported that metformin exerts beneficial effects on many neurological disorders, including major depressive disorder (MDD), Alzheimer’s disease (AD) and Fragile X syndrome (FXS); however, the mechanism underlying metformin in the brain is not fully understood. Neurotransmission between neurons is fundamental for brain functions, and its defects have been implicated in many neurological disorders. Recent studies suggest that metformin appears not only to regulate synaptic transmission or plasticity in pathological conditions but also to regulate the balance of excitation and inhibition (E/I balance) in neural networks. In this review, we focused on and reviewed the roles of metformin in brain functions and related neurological disorders, which would give us a deeper understanding of the actions of metformin in the brain.

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The safety and efficacy of metformin in fragile X syndrome: An open-label study

Cited by 21 publications

References 39 publications

EEG Signal Complexity Is Reduced During Resting-State in Fragile X Syndrome

EEG Signal Complexity Is Reduced During Resting-State in Fragile X Syndrome

Fragile X Syndrome: From Molecular Aspect to Clinical Treatment

Actions of Metformin in the Brain: A New Perspective of Metformin Treatments in Related Neurological Disorders

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