Fight against Multiple Sclerosis: a battle against demyelination

You can take the train to Chicago or you can take the plane to Chicago. So what happens if you somehow make a hybrid model of train and plane (call it trane) to get to Chicago? Do you get there faster or slower? Today, we are going to discuss a neuroscience paper from Hannover, Germany. Demyelination is the loss of myelin sheath in neurons. Myelin sheath is important in conducting signals in the complex neural network. If the myelin sheath is damaged, impairment in movement, coordination is observed. What is an example of demyelination disease? Multiple sclerosis is a prime example – it is one of the most common neurological disorders in youth adults. It is an immune-mediated demyelinating disease in the central nervous system (CNS).

In the paper, the authors ask what happens to the brain if you put two demyelinating agents together. Do you accelerate the process of demyelination?

There are two demyelinating agents tested in this paper: cuprizone and theiler virus. First, cuprizone is a chemical that chelates copper in the central nervous system. This leads to a lack of copper supply to neuronal cells. As copper is required for oligodendrocyte metabolism, oligodendrocytes (responsible for myelination) are dead. Thus, cuprizone leads to the death of oligodendrocytes, which indirectly shuts down the production of myelination. In contrast, theiler virus is a positive sense RNA virus that is grouped under the family of picornaviruses. Theiler virus DA strain causes chronic demyelination. During early phase of infection, the virus replicates in the gray matter of CNS. Later in infection, the virus persists in macrophage. At this stage, the virus induces demyelinating lesion, axonal damage, etc which resemble MS in human.

The paper had done a couple of experiments that support cuprizone in alleviating the CNS demyelination caused by Theiler virus. Cuprizone alone can cause demyelination in a specific region, known as corpus callosum. However, if you put cuprizone with theiler virus, the combination has a reduced demyelination in the thoracic spinal cord comparing to theiler virus infection alone. Look at the figure below, the bottom MBP panel shows you the presence of myelin basic proteins. Myelin basic proteins are responsible for myelination. You can see that there is a dramatic increase of myelin basic proteins in TMEV/CPZ (co-administration) comparing to TMEV (theiler alone). The co-administration also correlates with a better performance on the Rotarod scale (the Rotarod scale: place the mouse on a suspended rotating rod. This enables scientists to test the alertness, balance and the brain function of the mouse). Cuprizone also reduces the detectable amount of immune cells, such as B, T and macrophage during theiler infection. Since the immune system is down, scientists then ask if that allow the virus to replicate faster. The answer is no. In fact, the replication of theiler virus remains the same. This interesting paper has several insights in neuroinflammation. One, the cause of neuroinflammation must be caused by several factors. Two, theiler virus does not require neuroinflammation to remain persistent. Lastly, cuprizone reduces inflammation but does not affect virus replication.

Take home message:

The tug of war between cuprizone and theiler virus does sound fascinating. It is interesting to see if you put two demyelinating agents together, the effect turns out to be less effective than having theiler infection alone. It is hard to say who wins this tug of war, but it is definitely an innovative approach to study neurodegeneration using virus and chemical to induce demyelination.

Reference:

Cuprizone inhibits demyelinating leukomyelitis by reducing immune responses without virus exacerbation in an infectious model of multiple sclerosis.

Herder V, Hansmann F, Stangel M, Schaudien D, Rohn K, Baumgärtner W, Beineke A.

J Neuroimmunol. 2012 Mar;244(1-2):84-93. Epub 2012 Feb 12.

PMID: 22329906

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