2 agents against oxidative stress prevent CMT symptoms in mice

Two approved compounds, the antibiotic flfenicol and the antioxidant supplement MitoQ, prevented the development of symptoms in a mouse model of Charcot-Marie-Tooth disease (CMT), which was caused by mutations in the GDAP1 gene, a study shows.

In particular, these benefits have been linked to a reduction in oxidative stress, an imbalance between the production of potentially harmful reactive oxygen species (ROS) and a cell’s ability to detoxify them with antioxidants, resulting in cell and tissue damage.

Study results highlight oxidative stress as an important factor in GDAP1-associated CMT, such as types 4A and 2K, and help open clinical trials on whether these commercially available compounds can be reused to treat CMT, the researchers noted.

The study, “Effective therapeutic strategies in a preclinical mouse model of Charcot-Marie dental disease“Was published in the journal Human Molecular Genetics.

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Reusing compounds approved for one disorder to treat another will help “overcome the millionaire expense and decades-long chore” necessary to develop safe and effective treatment. Such efforts are particularly relevant for rare diseases “where pharmaceutical investments are scarce,” the researchers wrote.

A team of researchers in Spain used this strategy to treat CMT caused by GDAP1 mutations that have been shown to affect mitochondrial function and promote oxidative stress.

Problems in the mitochondria, the power plants of the cell, can increase the production of ROS and thereby increase oxidative stress.

The researchers therefore looked for active ingredients that support mitochondrial function from among 1,018 small compounds approved in the USA.

After a series of tests on laboratory-grown human cells with or without the GDAP1 gene, the researchers identified flfenicol, methylthiouracil and isosorbide as the best candidates, whose potential was further investigated in neurons from a mouse model of the GDAP1-associated CMT.

Florfenicol is a broad spectrum antibiotic mainly used in veterinary medicine, methylthiouracil was originally introduced to suppress hyperthyroidism and isosorbide to control heart disease.

Only flfenicol was found to significantly increase mitochondrial function in neurons from the mouse model compared to cells from healthy mice, suggesting that it could be a potential treatment for GDAP1-associated CMT.

Further analysis found that the antibiotic significantly reduced mitochondria-associated ROS production to a level comparable to that achieved with MitoQ, a mitochondria-targeted antioxidant sold as a dietary supplement.

While florfenicol treatment in the mouse model did not reduce disease severity when administered after symptoms onset, it was effective in preventing disease-related weight gain and motor deficits when started before symptoms appeared.

Similar results were observed when the mice were treated with MitoQ from early life (before the onset of symptoms).

Additional analyzes showed that the levels of enzymes involved in energy-producing mitochondrial functions and in the antioxidant response were significantly reduced in the peripheral sciatic nerves (the longest nerve in the body) of the CMT mouse model compared to those of healthy mice.

It is important that treatment with Florfenicol or MitoQ increased the levels of these enzymes and partially reduced the oxidative damage in the sciatic nerves.

These results support oxidative stress as the main contributor to CMT-associated nerve damage and indicate that both flfenicol and MitoQ prevent CMT development “by alleviating energy metabolism dysfunction and [oxidative damage] in peripheral nerves of a mouse model of CMT disease, ”the researchers wrote.

As such, these two compounds have the potential to be reused for the treatment of GDAP1-associated CMT and other types associated with excessive ROS production, such as CMT type 2A.

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