Tadpole model could be used to test remyelination therapies for MS

New lab model using tadpoles may help determine remyelination potential of new multiple sclerosis (MS) via specific changes in behavioral and vision tests, a new study suggests.

The model may help accelerate the discovery of potential MS remyelination therapies and reduce resource use on compounds that do not show effect.

“This model is…ideal for testing the remyelination potential of new drugs before initiating expensive and time-consuming clinical trials,” said Bernard Zalc, MD, of the Paris Brain Institute at Sorbonne University in France, in a statement. Press release.

The new model was described in the study, “Monitoring recovery after CNS demyelination, a new tool to reduce the risks of pro-remyelinating strategies,” Posted in Brain.

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MS is caused by inflammation of the brain and spinal cord, collectively called the central nervous system or CNS. This inflammation damages the fatty layer around the axons (nerve fibres) known as the myelin sheath.

“Myelin protects nerve fibers, ensures proper conduction of nerve impulses, and delivers nutrients to axons,” Zalc said. “This protective sheath envelops the nerve fibers and is essential for their proper functioning. His disappearance, called demyelinationcauses sensory and motor symptoms: weakness of the lower or upper limbs, loss of balance, sensitivity and visual disturbances.

While many MS treatments have been approved, all available therapies work by reducing inflammation. To date, no approved therapies have been proven to promote myelin repair (remyelination), and only a few experimental treatments have shown promising remyelinating effects in clinical trials.

Other experimental therapies have shown promise in early laboratory work, but testing these therapies in clinical trials of people with MS has yielded disappointing results.

According to Zalc, one potential explanation is that in laboratory models, compounds are typically evaluated on their ability to promote the growth and activity of oligodendrocytes, which are the cells primarily responsible for making and repairing myelin in the CNS. However, laboratory models have generally not investigated whether changes in oligodendrocyte activity are accompanied by objective evidence of improved nerve function.

“Why do candidate molecules consistently disappoint us when tested in humans? A possible explanation: at the preclinical stage, they are evaluated on their ability to generate new myelin-producing cells. This criterion, based on tissue observation, is not sufficient,” Zalc said. “For the drug to be effective, it must also improve the symptoms of the disease, or even completely restore sensory and motor skills.”

African clawed frog tadpoles

Here, Zalc and colleagues developed a new model to study remyelination using Xenopus laevis, the African clawed frog. When these frogs are born as tadpoles, their bodies are transparent, allowing researchers to view the CNS and other internal structures without harming the animal.

The scientists particularly focused their studies on the optic nerve – the main nerve that connects the eyes to the brain – because this part of the CNS is easily visible in tadpoles.

For this model, tadpoles were engineered so that their oligodendrocytes expressed two new proteins: one, a fluorescent marker allowing easier visualization of these myelin-producing cells, and the other, a bacterial enzyme called nitroreductase. . The researchers then treated the tadpoles with the chemical metronidazole.

This chemical is harmless on its own, but the enzyme nitroreductase converts metronidazole into a cell toxin. Thus, in this model, researchers could administer metronidazole to induce damage to oligodendrocytes and, consequently, loss of myelin. They could then stop giving the chemical to allow the oligodendrocytes to recover and remyelinate.

The researchers showed that metronidazole-induced myelin damage led to a significant reduction in swimming speed and distance traveled, and poorer performance in a test of visual avoidance (the tendency of tadpoles to avoid an image that looks like an obstacle in the water, a measure of eyesight in these animals).

When the drug was withdrawn and remyelination occurred, swimming speed and visual avoidance abilities again increased to normal levels.

“Our results show that variation in motor and sensory performance correlates perfectly with the level of tissue demyelination and remyelination,” Zalc noted.

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Testing the effects of two molecules, siponimod and clemastine

The team then used this animal model to test the effects of two molecules that have previously shown the ability to promote remyelination in laboratory models: siponimod, the active agent in the approved treatment for MS. mayzent; Or clemastinean antihistamine that is currently being tested in MS clinical trials.

The results showed that these compounds caused an increase in oligodendrocyte levels, but only clemastine treatment was associated with better performance on swimming speed, distance traveled and visual avoidance tests. Two other compounds known to have no impact on remyelination also did not significantly affect performance on functional behavior tests.

“Overall, these data support the utility of our conditional demyelination model for screening drugs for their ability to promote functional remyelination,” the scientists concluded.

“This new tool … has the potential to advance our knowledge of the link between visual disturbances – one of the most common symptoms of multiple sclerosis – and associated demyelinating lesions,” Zalc said. “It’s a real launching pad for future therapeutic successes.”