New model may prove better for testing remyelination drugs

mayo 04, 2023
There is an urgent need to find molecules capable of acting on demyelination, which, in its chronic form, leads to irreversible axon damage responsible for neuronal death. Researchers claim a new tool that allows in vivo monitoring has the potential to advance knowledge of the link between visual disorders – one of the most common symptoms of multiple sclerosis – and associated demyelination lesions.

Repairing myelin sheath lesions – or remyelination – is a real challenge, and clinical failures have multiplied over the years. Why are candidate molecules systematically disappointing when tested in humans? According to researchers at the Paris Brain Institute, one possible explanation is that at the preclinical stage, they are evaluated on their ability to generate new myelin-producing cells. This criterion, based on tissue observation, is insufficient. For the drug to be effective, it must also improve the symptoms of the disease or even completely restore sensory and motor capacities, the researchers explain. But at present, it is difficult to make the connection between a given demyelinating lesion and a specific sensorimotor deficit.

To fill this gap in understanding, the researchers used genetically modified Xenopus tadpoles, an amphibian with a perfectly transparent body at this stage of development. This feature makes it easy to count the number of myelin-producing oligodendrocytes within the optic nerve, then correlate this indicator with the motor and behavioral abilities of the animal.

Because changes in the number of oligodendrocytes indicate a process of demyelination or remyelination, the team developed a process to induce these events on demand. The researchers introduced a substance called metronidazole into the tadpole aquarium, which, under the conditions in which it was used, caused the loss of oligodendrocytes in the animals’ optic nerve. This loss was linked to impaired visual abilities. After exposure to metronidazole, researchers observed spontaneous myelin repair, as measured by an increase in the number of oligodendrocytes and improvement in visual test results. They then showed this phenomenon could be accelerated by presenting tadpoles with molecules that promote remyelination.

According to the researchers, the results show that variation in motor and sensory performance is perfectly correlated with the level of demyelination and tissue remyelination. Thus, this model is ideal for testing the remyelination potential of new drugs before launching long and costly clinical trials.

Results of animal model studies sometimes do not translate to humans and may be years away from being a marketable treatment. However, the researchers conclude that this approach is a real launchpad for future therapeutic success.

The findings were published in the journal Brain.
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