Sunday, 10 April 2016

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.

10 comments:

  1. Dear MD,

    Thanks for your blog about the cuprizone model.

    Bút I Think Prof G earlier on mentioned that this agent laquinimod had a profound effect in this Cuprizone model.

    Source:
    http://multiple-sclerosis-research.blogspot.com/2013/09/is-laquinimod-new-wonder-drug-that.html


    And MD,to your best knowledge, have anyone of the other agents (approved or experimenatal) showed any effect in this curpizone model, except for this experimental agent laquinimod ?

    Grateful for an answer, "to your best knowledge" on this question?

    Erica

    ReplyDelete
    Replies
    1. Dear Erica
      "Have any other agents worked in this model", in terms of experimental agents too many to mention have worked in this model but not the current DMT like fingo and DMF

      Delete
  2. MD, just a further clarifying from your side:

    So NON of the EXISTING APPROVED MS-agents has worked in this Cuprizone model, is that a correct interpretation ?

    ReplyDelete
    Replies
    1. There is limited logical reason why Current DMT would work in cuprizone model then I thought surely copaxone does everything:-).

      Sure enough
      Glatiramer promotes oligodendroglial cell maturation in a cuprizone-induced demyelination model. Rosato Siri MV, Badaracco ME, Pasquini JM.
      Neurochem Int. 2013 Jul;63(1):10-24

      Delete
  3. AND one more favour MD :-)

    Also MD, I would be grateful could mention another experimental agent in MS that had success in cuprizone model, but failed in the pivotal trial in Multiple Sclerosis. I want to know more about this agent and as an interested MS-patient try to compare the results


    E

    ReplyDelete
    Replies
    1. There have not been any pivotal trial published. You have to realise that remyelination is a new target so it probably needs a new trial design. When the current remyelination trials report we can dissect the approach more,

      Delete
  4. Dear MD,

    Seams like too obvious a question to ask: but if so little anti-lingo1 makes it into the cns why isn't it delivered intrathecally?

    ReplyDelete
    Replies
    1. yes seems like a sensible approaach, but if we read the post about rituximab going intrathecal is that this the bottom of the CSF drain so the flow from intrathecal is out of CNS, so it may not help. eg intrathecal baclofen does not get to the brain. I doubt people want intraventricular route

      Delete
    2. MD!
      Ok of The approved ms agents ONLY Copaxone has showed effect in The Cuprizone model, would that be correct interpreted from my side?

      Delete
    3. I didn,t check them all. We would need to go through them one by one and see if there is an effect and see how they compare. Go to pumed.org or google scholar and seach from name of drug and cuprizone and see what you get. There are quite alot for fingolimod. Biogen did a spoiler study.

      Please remember the default is remyelination and it occurs without any drug in the cuprizone model tye drug only speeds up the process. It is also interesting that this effect of cuprizone is a mouse thing

      I would not select a DMT based on this potential their job is to stop inflammation, do this early and effectively and the natural repair process is all that is needed

      Delete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.