Metformin for Treatment of Fragile X Syndrome and Other Neurological Disorders

Abstract

Fragile X syndrome (FXS) is the most frequent inherited form of intellectual disability and autism spectrum disorder. Loss of the fragile X mental retardation protein, FMRP, engenders molecular, behavioral, and cognitive deficits in FXS patients. Experiments using different animal models advanced our knowledge of the pathophysiology of FXS and led to the discovery of many targets for drug treatments. In this review, we discuss the potential of metformin, an antidiabetic drug approved by the US Food and Drug Administration, to correct core symptoms of FXS and other neurological disorders in humans. We summarize its mechanisms of action in different animal and cellular models and human diseases.

Fragile X Syndrome and Targeted Treatments

“…Metformin lowers the level of blood glucose by enhancing peripheral glucose uptake and glycolysis while inhibiting hepatic gluconeogenesis and gastrointestinal glucose absorption. 3 The reduction of blood glucose causes a decrease of insulin signaling and consequently inhibits the mechanistic target of rapamycin complex 1 (mTORC1) and MAPK/ERK pathways. Moreover, metformin also inhibits the mTORC1 and ERK pathways via activation of AMPactivated protein kinase complex (AMPK) 3 .…”

“…3 The reduction of blood glucose causes a decrease of insulin signaling and consequently inhibits the mechanistic target of rapamycin complex 1 (mTORC1) and MAPK/ERK pathways. Moreover, metformin also inhibits the mTORC1 and ERK pathways via activation of AMPactivated protein kinase complex (AMPK) 3 . MMP-9 which is upregulated in conditions of FMRP deficiency causes a negative impact on synaptic formation in FXS.…”

“…Metformin stimulates neurogenesis in animal models. 3 Normalizing the excess protein production in the CNS in FXS with metformin leads one to predict that young children may demonstrate the greatest benefits from metformin treatment. A case series report of 9 children between 2-7 years old has recently illustrated benefits of metformin in both developmental and behavioral domains.…”

Cognitive and behavioral improvement in adults with fragile X syndrome treated with metformin‐two cases

“…The symptoms in patients with fragile X syndrome (FXS; phenotype MIM number: 300624) are related to the absence or deficiency of FMRP, a protein which plays a key role in protein translation which is important for neuronal synaptic connections. There is an upregulation of the metabotropic glutamate 5 (mGluR5) pathway, the insulin receptor and the mTOR pathway in the absence of FMRP (Gantois, Popic, Khoutorsky, & Sonenberg, 2019;Hagerman et al, 2017). This dysregulation leads to global developmental delays in males and continued IQ decline in childhood and adolescence (Wright-Talamante et al, 1996).…”

“…The use of metformin in the animal models, such as Drosophila FXS and FXS knock out (KO) mouse demonstrated that metformin could improve FXS phenotypes, the circadian rhythm deficits and memory deficits (Gantois et al, 2017;Monyak et al, 2017). Pathogenically overactive signaling pathways in FXS in the central nervous system could also be normalized by metformin (Gantois et al, 2017(Gantois et al, ,2019.…”