Better repaired nerve insulation may lead to new multiple sclerosis treatments

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In a new study in mice, researchers from Johns Hopkins Medicine found a better way than natural cure to repair damaged insulation around nerve cells. Usually, with each repair, the natural healing process adds bumps to the surface of the protective layer of fat called myelin. Over time and after cumulative damage, the myelin ultimately becomes too misshapen to wrap neatly around the nerve, causing it to lose its function.

This happens in multiple sclerosis (MS), a disorder where the body’s immune system mistakenly attacks the myelin around the nerves, turning them off, and causing communication problems between the brain and the rest of the body.

In their study, published October 2, 2020 in Science Advances, the researchers say the use of certain drugs can prevent relapsing-remitting MS, the intermittent form of the disorder, from turning into progressive MS – a chronic form of the disease that involves myelin can no longer repair itself.

“Immune system suppression has helped treat relapsing-remitting MS, but does not protect against the potential rise to progressive MS, for which there are no good treatments on the market,” says Norman Haughey, Ph.D. , Professor of Neurology at Johns Hopkins University School of Medicine. “We believe these results are a huge step towards improving the quality and composition of myelin after a flare-up.”

In previous work by Haughey’s team, researchers looked at the makeup of the myelin surrounding nerves found near injured brain tissue from those who died with MS. Myelin is primarily made up of hundreds of types of fat molecules and proteins. The researchers found that myelin around nerves near injury sites looked misshapen compared to other nerves, along with much higher levels of ceramide – a specific type of fat molecule – and lower levels of another fat molecule called sulfatide.

The right amount of ceramide is especially important as this fat regulates the curvature of the myelin – too much ceramide and it cannot wrap itself tightly around the nerve, causing “bumps” in the myelin.

In the new study, the researchers fed mice the drug cuprizone for 26 days to damage the myelin on their nerve cells. The myelin repaired itself but looked bumpy and wrapped badly around the nerve from the excess ceramide. In a series of experiments, the researchers found that encephalitis activates the enzyme neutral sphingomyelinase-2, which produces ceramide.

Working with an experienced drug development team led by Barbara Slusher, Ph.D., MAS, professor of neurology at Johns Hopkins University Medical School, researchers identified the small molecule drug cambinol, which blocks the effects of neutral sphingomyelinase-2. They hypothesized that this would prevent excess ceramide from being made and built into the regenerated myelin after an injury.

After feeding their mice cuprizone for nearly a month to cause myelin damage, the researchers injected them with cambinol. This time when the myelin grew back, it wrapped itself tightly around the neurons and looked like it did before the damage.

The researchers say that this intervention did not fully restore the myelin’s fat composition, but appeared to increase the myelin’s stability, which would likely better protect the underlying neurons.

The team needs to determine if the repaired myelin is affecting other abnormal fat levels, even if excessive ceramide formation is prevented. Researchers also need to confirm that once myelin is in its correct form and structure, it works as it should and is more stable over long periods of time.

Once this is done, the team hopes to develop small-molecule inhibitors of the neutral sphingomyelinase-2 for later use in human studies.

Postdoctoral fellow Seung-Wan Yoo, Ph.D., MS, is the lead author of this study.

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More information:
Seung-Wan Yoo et al. Inhibiting neutral sphingomyelinase 2 promotes remyelination, Science Advances (2020). DOI: 10.1126 / sciadv.aba5210 Provided by the Johns Hopkins University School of Medicine

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