Metformin Reversed Symptoms Associated with Huntington’s Disease in Mouse Study

Metformin Reversed Symptoms Associated with Huntington’s Disease in Mouse Study
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Researchers narrowing in on early neuronal functioning stages of development, well before Huntington’s disease symptoms appear, believe they have found a potentially important path to intervening with the diabetes medication metformin. Their research was conducted in a mouse model of the disease.

Metformin, an oral medication normally prescribed to patients with diabetes mellitus type 2 to control blood sugar levels, was seen to decrease the production and accumulation of the mutant form of the huntingtin protein and to prevent neuronal dysregulation and behavioral defects in the mice.

The study, “Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease,” was published in eLIFE.

Huntington’s disease is a genetic, neurodegenerative disorder characterized by the expansion of a CAG repeat in the huntingtin gene (HTT), causing a mutant protein (mHTT). This protein is broken down into small pieces that clump together, forming toxic protein aggregates inside nerve cells that interfere with their normal function and, ultimately, lead to cell death.

Huntington’s has several stages, including an initial pre-symptomatic phase in which patients experience no symptoms. This is followed by an early stage that can last up to eight years, in which patients do not experience motor impairments but might already suffer from mild cognitive and psychiatric symptoms. These may include a lack of social interaction and concentration deficits accompanied by subtle neuronal dysregulation.

Mild changes in neuronal function can occur even earlier, in a phase known as “very far from disease onset,” or VFDO, also a pre-symptomatic phase. This phase can happen 15-20 years before the onset of motor symptoms, long before mHTT protein aggregates and signs of neurodegeneration become apparent.

Detecting functional alterations and tackling these issues during the VFDO phase could be key to developing preventive therapies to minimize the neuronal loss experienced in Huntington’s disease, the researchers said.

They analyzed specific circuits of neurons located in the visual cortex, one of the first brain regions affected by Huntington’s disease, during theVFDO phase.

In vivo two-photon calcium imaging revealed that young adult animals (10-15 weeks old) still in the pre-symptomatic stage of disease already showed signs of neuronal circuit dysregulation in the visual cortex, characterized by an abnormal increase in neuronal activity and synchronicity. This imaging technique allows investigators to spot fluorescent calcium indicators inside cells that can be used as a “landmark” to reconstruct the structure of neuronal circuits.

These structural alterations were also accompanied by significant changes in animal behavior, including anxiolytic behavior.

Previous studies by the same team already suggested that metformin could interfere with the production of mutant huntingtin. Therefore, it could be considered a promising candidate to reduce protein accumulation and even reverse some of the symptoms associated with Huntington’s disease.

To test this hypothesis, researchers first treated in vitro cultured human embryonic kidney (HEK) cells that expressed the mutant huntingtin protein with different concentrations of metformin. They found that the compound was able to reduce the levels of mHTT in a concentration-dependent manner.

Then, scientists fed VFDO Huntington mice with 5 mg/ml of metformin diluted in water. Remarkably, after three weeks of treatment, neuronal circuit abnormalities and behavioral defects were fully restored in animals fed with metformin.

Together, these findings indicate that by directly interfering with the production of mHTT, metformin is a promising therapeutic candidate for preventive therapy during the pre-symptomatic and early stages of the disease.

“Our data suggest that metformin has the potential to reduce mHtt [mutant huntingtin] protein load and substantially influence the early development of [the disease]. … It is an inexpensive substance, well known in long-term clinical usage and has a defined, relatively benign spectrum of side effects,” the authors wrote.

“Prescription to mutation carriers from young adulthood on (or even earlier) is possible and will cover these newly discovered critical windows of opportunity for therapy,” they concluded.

The post Metformin Reversed Symptoms Associated with Huntington’s Disease in Mouse Study appeared first on Huntington’s Disease News.

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