Could tadpoles help in the search for remyelination therapies for MS?

Scientists have developed a new laboratory model using tadpoles that can help discover remyelination abilities of new therapies for multiple sclerosis (MS), a new study reports.

Researchers said the model would be useful to test the remyelination potential of drugs before long and costly clinical trials are launched.

All current therapies for MS reduce inflammation – finding a drug that can stimulate remyelination, which would repair the damage done to the brain and spinal cord done by MS, is something researchers are keen to do.

Early lab work often shows promise in this area, but then disappoints when tested in humans. Researchers said this might be because therapies are investigated for their ability to promote growth of oligodendrocyte cells, which make myelin, but tests haven’t thoroughly explored whether this oligodendrocyte activity leads to better nerve function. The researchers in this study said for a drug to be effective it must be able to improve symptoms of disease.

The study used tadpoles of the African clawed frog which, when born, have transparent bodies which allowed the researchers to see the central nervous system and other internal structures of the animal without hurting it.

For this model, the tadpoles were engineered so that their oligodendrocytes would express two new proteins. One was a fluorescent marker to allow researchers to see myelin-making cells, and two, a bacterial enzyme called nitroreductase. The researchers then treated the tadpoles with the chemical metronidazole.

When this chemical meets nitroreductase it converts into a cellular toxin which induces oligodendrocyte damage and myelin loss. They could then stop the chemical, allowing the cells to recover and remyelination to occur.

The researchers showed that metronidazole-induced myelin damage reduced swimming speed and distance travelled, and poorer performance on a test of visual avoidance (the tadpoles’ avoidance of an image that looks like an obstacle in the water, a measure of their sight).

When the drug was withdrawn and remyelination occurred, swimming speed and visual avoidance abilities increased again to normal levels. The researchers said these results showed that variation in motor and sensory performance is correlated with the level of demyelination and tissue remyelination,

They then tested two molecules that have been demonstrated in previous studies to have the ability to promote remyelination in laboratory settings – clemastine, an antihistamine being currently tested in clinical trials for MS, and Siponimod, the active ingredient in the MS therapy Mayzent.

Both of the molecules increased oligodendrocyte levels, but clemastine was accompanied by faster swimming and distance travelled.

“Altogether these data confirm the usefulness of our conditional demyelination model to screen drugs for their potency to promote functional remyelination,” the researchers concluded.