Multiple models and tools are bringing the vicious cycle of MS into better focus. Read how our scientists are using them.

One of the key lessons in drug development is this: Disease is complicated. So the notion that a single animal model could ever represent the way the disease runs its course in a single individual, let alone an entire population, is, quite simply, naïve.

Consider multiple sclerosis (MS), a chronic, usually progressive disease that attacks and destroys the myelin or fatty sheath surrounding nerve cells. Over 2 million people suffer from MS worldwide, one of the most common in a collection of disorders known as demyelinating diseases. But like so many other conditions, MS comes in different forms. Some strains are harsher than others. There is relapsing MS, where the myelin continually degrades and then replenishes itself, though coming back with less and less vigor over time. There are also primary and secondary progressive forms of MS, where there is little if any alleviation from symptoms that range from tremors, numb or weak limbs, and vision problems to tingling limbs, pain, and slurred speech.

For years, drug developers have relied on the experimental autoimmune encephalomyelitis (EAE) model to test new MS therapies. MS has long been thought to be an autoimmune disorder, influenced by an onslaught of inflammatory cells that infiltrate and degrade the myelin sheath and prevent nerve cells from transmitting signals to the brain. By inducing brain inflammation, EAE has allowed researchers to study the autoimmune effects of MS, and develop new drugs to combat neurological inflammation and improve relapse rates.

But the EAE doesn’t allow researchers to look at demyelination independently of the autoimmune effects, which impedes the discovery of compounds designed to specifically interfere with this process. In recent years, pharmaceutical manufacturers have begun using a cuprizone model named for a copper-chelating agent that is toxic to the oligodendrocytes that produce myelin. Mice usually undergo the process of demyelination after consuming mouse chow mixed with a small amount of cuprizone.

“The myelin is basically degraded when cuprizone affects myelin forming cells, oligodendrocytes, which means the neurological impulses are slowed down and impaired,” says Antti Nurmi, Director of Science, Operations at Charles River’s Discovery Research Services site in Finland.

Three separate poster presentations presented Sunday at the Society for Neuroscience meeting in Chicago by Nurmi and his Finnish colleagues describe how they used the cuprizone model in mice to characterize behavior, inflammatory changes and changes in brain matter using an assortment of tools ranging from high-tech mouse mazes and kinematic analysis to Magnetic Resonance Imaging (MRI) and Single Photon Emission Computed Tomography (SPECT).

One study used five different behavioral tests to measure functional changes and disease phenotype in mice exposed to cuprizone compared to matched controls. Nurmi said they found “fairly robust behavioral” changes in the mice—their motor performance, gait and coordination declined—but when the cuprizone was removed from their diet symptoms improved. This allows them to examine also process called remyelination, which is an active process counter-balancing cuprizone-induced demyelination.

Another study used three different imaging tests to actually visualize changes in the white matter and tissue of mice challenged with cuprizone when compared to controls. White matter contains heavy concentrations of myelinated axons—the area where nerve impulses are conducted—but in the Cuprizone model, there was evidence of widespread inflammation and drop in brain composition and connectivity suggesting robust demyelination.

A third study analyzed the pathological changes in cuprizone mice using immunohistochemical and flow cytometry.

The cuprizone model isn’t perfect and it certainly doesn’t solve or even complete the MS puzzle. Whether we move closer to understanding what sets the devastating cycle of demyelination in motion is still a black box. As we said earlier, disease is complicated.

What’s perhaps is clearer, not just with MS but with other diseases, is the need for multiple endpoints and multiple animal models so that drug developers can pluck, with greater confidence, a promising drug compound from the lineup.

The cuprizone model represents another tool in the toolbox.

SfN Postscript: Art Imitating Science

Lia Cook artworkThe SfN meeting is all about the neuroscience, but sometimes you can find cerebral connections in art. San Francisco artist Lia Cook, who has been working in textiles for decades, became interested several years ago in exploring the emotional connections that she noticed people were forming after viewing her close-ups of dolls’ and children’s faces. Even though Cook is not a scientist, she developed a study in collaboration with the University of Pittsburgh that used diffusion tensor imaging (DTI)—a type of MRI—and other imaging tools to monitor the brain activity of individuals as they viewed both photographs and woven images of the same faces.

Using these imaging tools they were able to generate data—pupil dilation for instance—that indeed suggested that people had a low-level emotional reaction to the woven images compared to the photographs. Cook was displaying some of her textile creations—which take anywhere from a week to 30 days to make—outside the Exhibit Hall at the SfN meeting in Chicago. Many are woven images of her around the age of four, masked by what appear to be tangles of dendrites. Spooky and fascinating, like a puzzle waiting to be solved.

How to cite:

McEnery, Regina. The Myelin Shield. Eureka blog. Oct 19, 2015. Available: