Diabetes Therapy Metformin Restores Brain Energy in Rett Mouse Model

Inês Martins, PhD avatar

by Inês Martins, PhD |

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Treatment with the diabetes therapy metformin is able to restore energy production in the brain and reduce oxidative stress associated with Rett syndrome, a study in mice suggests.

Yet, the therapy failed to ease motor symptoms in animals with fully developed disease, stressing the need for more research on earlier and prolonged treatment with metformin, the researchers said.

The study, “The Anti-Diabetic Drug Metformin Rescues Aberrant Mitochondrial Activity and Restrains Oxidative Stress in a Female Mouse Model of Rett Syndrome,” was published in the Journal of Clinical Medicine.

Metformin is best known for reducing blood glucose — high blood sugar levels — in the treatment of diabetes. However, emerging research is showing that it also may correct the abnormal function of mitochondria, which are the powerhouses of the body’s cells, and protect against toxic free radicals that cause oxidative stress.

This research points to Metformin’s therapeutic potential across other diseases, including Rett.

Rett syndrome is a rare neurodevelopmental disorder characterized by motor, social and cognitive impairments that begin in the first years of life. It typically affects girls. While the mechanisms leading to disease are not fully understood, researchers believe that defective energy production in mitochondria and oxidative stress play a role in Rett syndrome progression.

People with Rett also seem to have alterations in metabolism, showing elevated levels of fat molecules and insulin resistance — which may cause diabetes.

Metformin could thereby help Rett patients by improving metabolism and mitochondrial function. In addition to having an established safety profile, metformin can be used in children and has the ability to cross the blood-brain-barrier, potentially correcting disease mechanisms in the brain.

To address the benefits of metformin in Rett, researchers in Italy used an established mouse model carrying mutations in the MECP2 gene — which cause Rett in humans — as well as control animals. Metformin was administered for 10 days when the mice (all female) reached one year of age, which is when full symptoms mimicking alterations in Rett are evident.

Treatment with metformin restored energy production in mitochondria, the results showed. In addition, metformin brought energy levels in the brain back to normal levels, by increasing the production and activity of proteins involved in energy synthesis.

Reactive oxygen species are free radicals that often result from abnormal mitochondrial function. They target other cellular components, causing damage to cells. In Rett, such toxic molecules are often found in higher-than-normal levels. Metformin was able to lower their levels in the brain back to normal.

The team then found that metformin was exerting its effects by activating proteins involved in protecting the body from oxidative stress and in the remodeling and formation of new mitochondria.

Interestingly, the scientists said, metformin did not activate the same mechanisms in control mice. That was consistent with prior studies reporting that the therapy’s effects on mitochondria are dependent on the initial energy status.

Animals treated with metformin, however, did not experience any benefits in motor function. There were no improvements in locomotion, coordination, or balance.

These findings may owe to the advanced disease stage of the animals and the short treatment duration, the researchers said. But they said the lack of benefits also may be due to the fact that mitochondrial abnormalities precede motor changes.

Earlier and prolonged treatment with metformin could therefore be needed for greater benefits, they said.

“Even though further studies are needed to uncover the underlying molecular mechanisms and the most suitable time window for metformin administration, this study suggests that [Rett] patients may benefit from metformin administration, thus opening a new window of therapeutic opportunities,” the team concluded.