Fragile X syndrome is a
genetic disease caused by defects in the Fragile X Mental Retardation 1 gene
(FMR1), which triggers excess production of protein in the brain, as well as
dysregulated connections between neurons and changes in behavior. The condition
leads to impairments in speech and language, behavior and social interaction.
It affects about 1 in 5,000 boys and 1 in 6,000 girls and is often co-diagnosed
with autism, anxiety disorders and seizures. I have never personally worked on
the Fragile X syndrome but I have indirectly been associated with ongoing
research efforts about this disease through a close friend of mine and an accomplished
neuroscientist Dr. Udai Bhan Pandey, currently an associate professor of Human
Genetics at University of Pittsburgh. Earlier in his career, Dr. Pandey worked on
Fragile X syndrome for his Ph.D. dissertation in the same lab in which I was
working on a GI cancer model. I vividly
remember how passionately he used to talk about this disease and as to how
there is no cure for fragile X syndrome back in 2003. Even today after 14 years,
there is no cure yet.
A new study led by
researchers at McGill University, the University of Edinburgh and Université de
Montréal has found that Metformin improves social, behavioral and morphological
defects in mice model of Fragile X syndrome. For those who are not aware about Metformin,
it is a common drug used in individuals with high risk for diabetes type 2,
obesity or impaired glucose tolerance. It has had a strong safety profile in
children and adults with type 2 diabetes and obesity.
Ilse Gantois, Arkady
Khoutorsky, Jelena Popic, Argel Aguilar-Valles, Erika Freemantle, Ruifeng Cao,
Vijendra Sharma, Tine Pooters, Anmol Nagpal, Agnieszka Skalecka, Vinh T Truong,
Shane Wiebe, Isabelle A Groves, Seyed Mehdi Jafarnejad, Clément Chapat, Elizabeth
A McCullagh, Karine Gamache, Karim Nader, Jean-Claude Lacaille, Christos G
Gkogkas, Nahum Sonenberg. Metformin ameliorates core deficits in a mouse
model of fragile X syndrome. Nature Medicine, 2017; DOI: 10.1038/nm.4335
In this study, Gantois et
al. beautifully demonstrate that metformin, a type II diabetes drug that crosses
the blood-brain barrier, corrects various neurological and behavioral
phenotypes of fragile x syndrome in a mouse model known as Fmr1−/y. These
mice have increased abundance of an kinase (a type of cellular enzyme) known as RAF and enhanced activity of its related kinases and gene targets. These investigators found that a chronic
(10-day) treatment with metformin reduced the abundance of RAF and suppressed
the activation of enzymes such as MEK, ERK, mTOR, and
translation initiation factor eIF4E in the prefrontal cortex and hippocampus of Fmr1−/y mice which are important molecules in the pathogenesis of fragile X disease.
Decreased mTOR activity correlates with decreased expression of the gene
encoding MMP9, a protease (another type of enzyme) that regulates synaptic function. Metformin
suppressed repetitive behavior, the incidence of macroorchidism, and defects in
dendritic spine development and synaptic activity in Fmr1−/y mice,
phenotypes that are common in fragile x syndrome patients.
Please note that this study
is conducted in mice model, and in spite of lot of similarities between mice
and human, further tests will be needed to assess whether metformin can
specifically improve cognitive function in mammals and assess the extent of its
benefits versus its side effects which are many. Yet scientific community is
very optimistic about these findings suggesting that metformin might be
repurposed for use in fragile x patients.
Dr. Nahum Sonenberg, a pioneering scientist of our times, best known for his seminal contributions to our
understanding of translation of proteins from RNAs, and notable for the discovery of the mRNA 5'
cap-binding protein, eIF4E, the rate-limiting component of the eukaryotic
translation apparatus and also a senior author of this research work says about
Metformin: "Basically, it's something like a wonder
drug,"
https://en.wikipedia.org/wiki/Nahum_Sonenberg
'Wonder drug' in the past
few years, metformin has generated extensive interest for its potential in
treating numerous health problems such as cancer, cardiovascular diseases, neurological
diseases and aging. Numerous preclinical, epidemiological and clinical studies
in the past have suggested that metformin use is associated with inhibition of
cancer cell growth and reduction in all-cancer incidents in comparison with
users of other hypoglycemic drugs. So if you are type 2 diabetes patient and
your doctor has advised you to take metformin, you have another good reason to
keep taking this drug regularly without fail.
http://www.healthline.com/health/metformin-oral-tablet#about3
