Friday, 10 October 2014

New Model of Demyelination

Sachs HH, Bercury KK, Popescu DC, Narayanan SP, Macklin WB
A new model of cuprizone-mediated demyelination/remyelination.
ASN Neuro. 2014 ;6(5). pii: 1759091414551955. doi: 10.1177/1759091414551955. Print 2014.

Because of the lack of effective remyelination in the adult human brain. One model used to understand the mechanisms regulating remyelination is cuprizone-induced demyelination, which allows investigation of remyelination mechanisms in adult animals following toxin-induced demyelination. Unfortunately, the degree of demyelination in the cuprizone model can vary, which complicates understanding the process of remyelination. Previous work in our laboratory demonstrated that the Akt/mTOR pathway regulates active myelination. When given to young postnatal mice, the mTOR inhibitor, rapamycin, inhibits active myelination. 

In the current study, the cuprizone model was modified by the addition of rapamycin during cuprizone exposure. When administered together, cuprizone and rapamycin produced more complete demyelination and provided a longer time frame over which to investigate remyelination than treatment with cuprizone alone. The consistency in demyelination will allow a better understanding of the mechanisms initiating remyelination. Furthermore, the slower rate of remyelination provides a longer window of time in which to investigate the diverse contributing factors that regulate remyelination. This new model of cuprizone-induced demyelination could potentially aid in identification of new therapeutic targets to enhance remyelination in demyelinating diseases.

Useful models of remyelination are needed. In animals and probably in humans too the default pathway after demyelination is remyelination. The problem is that is you do nothing in the animal models remyelination occurs anyway in a few weeks, so it is difficult to get much of a therapeutic effect with drugs. In this study they added rapamycin and this was slow. This gives you more time to see an effect. The paper is open source so you can read if interested.

Sirolimus, also known as rapamycin, is a macrolide (one of a group of drugs containing a macrolide ring) produced by the bacteria Streptomyces hygroscopicus. It has immunosuppressant functions in humans and is used to prevent rejection in organ transplantation. It has been reported that this inhibits EAE in quite few studies, however based on this then you would predict it inhibits repair. This hightlighs a common theme that the molecules that drive remyelination have many other functions in the body and so promoting repair may have unwanted side-effects...I hear you say so what's new. Yep every thing is a balance

1 comment:

  1. Demyelination without accompanying inflammation is very far from the MS situation. It's always been interesting to me that the remyelinators avoid repeating their findings in EAE as if their scared that this will confound their carefully constructed hypothesis.


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