Chemical Demyelination

Tagge I, O'Connor A, Chaudhary P, Pollaro J, Berlow Y, Chalupsky M, Bourdette D, Woltjer R, Johnson M, Rooney W. Spatio-Temporal Patterns of Demyelination and Remyelination in the Cuprizone Mouse Model.PLoS One. 2016 Apr 7;11(4):e0152480.

Cuprizone administration in mice provides a reproducible model of demyelination and spontaneous remyelination, and has been useful in understanding important aspects of human disease, including multiple sclerosis. In this study, we apply high spatial resolution quantitative MRI techniques to establish the spatio-temporal patterns of acute demyelination in C57BL/6 mice after 6 weeks of cuprizone administration, and subsequent remyelination after 6 weeks of post-cuprizone recovery. MRI measurements were complemented with Black Gold II stain for myelin and immunohistochemical stains for associated tissue changes. Gene expression was evaluated using the Allen Gene Expression Atlas. Twenty-five C57BL/6 male mice were split into control and cuprizone groups; MRI data were obtained at baseline, after 6 weeks of cuprizone, and 6 weeks post-cuprizone. High-resolution (100μm isotropic) whole-brain coverage magnetization transfer ratio (MTR) parametric maps demonstrated concurrent caudal-to-rostral and medial-to-lateral gradients of MTR decrease within corpus callosum (CC) that correlated well with demyelination assessed histologically. Our results show that demyelination was not limited to the midsagittal line of the corpus callosum, and also that opposing gradients of demyelination occur in the lateral and medial CC. T2-weighted MRI gray/white matter contrast was strong at baseline, weak after 6 weeks of cuprizone treatment, and returned to a limited extent after recovery. MTR decreases during demyelination were observed throughout the brain, most clearly in callosal white matter. Myelin damage and repair appear to be influenced by proximity to oligodendrocyte progenitor cell populations and exhibit an inverse correlation with myelin basic protein gene expression. These findings suggest that susceptibility to injury and ability to repair vary across the brain, and whole-brain analysis is necessary to accurately characterize this model. Whole-brain parametric mapping across time is essential for gaining a real understanding of disease processes in-vivo. MTR increases in healthy mice throughout adolescence and adulthood were observed, illustrating the need for appropriate age-matched controls. Elucidating the unique and site-specific demyelination in the cuprizone model may offer new insights into in mechanisms of both damage and repair in human demyelinating diseases.

If you are hoping for a remyelinating drug.You may want to read this paper. This model is often tested in the cuprizone model. In mouse strains this will kill off oligodendrocytes in mouse brains notably in the corpus callosum which is the nervous highway bewteen the left and right side of the brain. Here they use MTR magnetization transfer ratio as an approximation of myelination but in this study it reports it is age depenedent. You may want to read this. Cuprizone is supossed to affect the cerebellum but there is not much (red) activity in the cerebellum.

They stain for myelin and  you see  myelin loss (look in B)
In the model you feed cuprizone. Myelin is lost. Stop feeding and there is remyelination. Give a drug remyelination occurs quicker.
This is post-inflammatory repair and so the translational aspect is to give after a relapse and then there should be better recovery. However, what you want to see is remyelination of chronic demyelinated, gliotic lesions? 

So my mind this has never been attempted in animals, or if it has it  has never been reported. Yet we are waiting for the read-out of the anti-LINGO trial in progressive MS.

So if it success then it is all down to the pre-clinical studies, but if it fails don't blame the animals. The anti-LINGO trial is delivering a drug where 99.9% is wasted because it never reaches the target using endpoints designed for relapsing remitting trials and MRI surrogates that abit loose. If remyelination occurs in animals it is complete in about 3 weeks, yet the trials are for 2 years. How much improvement are we going to see...Just keeping it real....but let's hope for a fantasical result.