Diabetes Therapy Metformin Boosts Cognitive Flexibility in Rett Mice

Benefits found in mice at advanced disease stages, researchers note

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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An oversized hand is shown holding a laboratory mouse next to a trio of vials of blood.

Treatment with the diabetes medication metformin for four months led to cognitive improvements and restored brain energy production in a mouse model of Rett syndrome, a study found.

Notably, the therapy’s benefits were observed when administered in a relatively advanced stage of disease — one in which the mice were already affected by significant motor, cognitive and general health symptoms.

Still, the therapy was not able to restore general health, motor coordination, or spatial memory in the mice, according to researchers.

The findings overall offer “innovative evidence that a chronic treatment with metformin rescues cognitive flexibility deficits and provides long-lasting beneficial effects on brain metabolic dysfunction in a [Rett] mouse model,” the team wrote.

The study, “Chronic treatment with the anti-diabetic drug metformin rescues impaired brain mitochondrial activity and selectively ameliorates defective cognitive flexibility in a female mouse model of Rett syndrome,” was published in the journal Neuropharmacology.

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Diabetes Therapy Metformin Restores Brain Energy in Rett Mouse Model

Exploring metformin for Rett syndrome

Metformin is a commonly used medication to lower blood sugar levels in people with type 2 diabetes.

Beyond diabetes, a growing body of evidence suggests that metformin may have beneficial effects in the brain. The medication has been shown to ease cognitive dysfunction in people with diabetes, as well as offer neuroprotection in preclinical models of stroke and Alzheimer’s and Parkinson’s diseases.

While the mechanisms by which metformin acts aren’t fully established, it’s thought that it may work, in part, by modulating the function of mitochondria — the energy production centers of cells.

Proper function of mitochondria is critical in the brain, which demands a large proportion of the body’s energy production.

Altered mitochondrial function has been described in a number of brain disorders, including Rett syndrome, for which “maintenance of normal brain energy metabolism may represent a crucial opportunity for treatment intervention,” the researchers wrote.

In a previous study, published in 2021, the researchers found 1o days of metformin treatment could normalize mitochondrial energy production and increase levels of ATP — the molecule that serves as a cellular energy source — throughout the brain in a mouse model of Rett.

The treatment also reduced signs of oxidative stress, a type of cell damage marked by the overproduction of reactive oxygen species (ROS) that outweighs the levels of antioxidants to combat them.

But still, these changes were not associated with fewer Rett-like symptoms.

Now, the team aimed to examine whether longer-term treatment with metformin would have more beneficial effects on Rett behavioral symptoms.

As in the previous study, 1-year-old fully symptomatic female Rett mice were used. At this age, mice exhibit mild motor abnormalities and significant alterations in learning and memory.

The mice were treated for four months with metformin, which was dissolved in tap water. Healthy, or wild-type female mice also were given either metformin or normal water.

Over the course of the study, the mice underwent a battery of behavioral tests to evaluate the effects of the treatment. This battery included tests of general health, motor coordination, memory, and cognitive flexibility.

Results showed that Rett mice had compromised general health and impaired motor coordination compared with their wild-type counterparts, and metformin treatment failed to ease these symptoms. Likewise, the treatment did not improve memory performance.

In contrast, metformin did demonstrate an ability to ease cognitive flexibility defects in the Rett mice. Cognitive flexibility refers to the ability of the mouse to change its behavior based on its surroundings.

The findings offer “innovative evidence that a chronic treatment with metformin rescues cognitive flexibility deficits and provides long-lasting beneficial effects … in a [Rett] mouse model

At the end of the treatment period, brain tissue and blood were analyzed to assess mitochondrial function and oxidative stress.

The metformin treatment was associated with a restoration of mitochondrial activity and ATP production in the brain, which were impaired in the Rett mice.

Production of ROS in the blood also was decreased after treatment, reflecting a decline in oxidative stress. Pathways associated with mitochondria production and antioxidant defense systems were boosted in the brain with metformin treatment.

Overall, the findings “shed new light on the potential therapeutic applications of metformin, highlighting its potential use for the treatment of intellectual disability disorders characterized by brain mitochondrial dysfunction,” the researchers wrote.

The team noted that further studies will be needed to better establish the treatment’s potential for Rett. A particular focus should be on whether an earlier intervention may have beneficial effects on other symptoms of the neurodevelopmental disorder.