Feng Mei, Klaus Lehmann-Horn ,Yun-An A Shen, Kelsey A Rankin, Karin J Stebbins, Daniel S Lorrain ,Kara Pekarek,
Sharon A Sagan, Lan Xiao, Cory Teuscher, H-Christianvon Büdingen, Jürgen Wess, J Josh Lawrence, Ari J Green, Stephen PJ Fancy, Scott S Zamvil, Jonah R Chan
Accelerated remyelination during inflammatory demyelination prevents axonal loss and improves functional recovery
DOI: http://dx.doi.org/10.7554/eLife.18246 eLife 2016;5:e18246
Demyelination in MS disrupts nerve signals and contributes to axon degeneration. While remyelination promises to restore lost function, it remains unclear whether remyelination will prevent axonal loss. Inflammatory demyelination is accompanied by significant neuronal loss in the experimental autoimmune encephalomyelitis (EAE) mouse model and evidence for remyelination in this model is complicated by ongoing inflammation, degeneration and possible remyelination. Demonstrating the functional significance of remyelination necessitates selectively altering the timing of remyelination relative to inflammation and degeneration. We demonstrate accelerated remyelination after EAE induction by direct lineage analysis and hypothesize that newly formed myelin remains stable at the height of inflammation due in part to the absence of MOG expression in immature myelin. Oligodendroglial-specific genetic ablation of the M1 muscarinic receptor, a potent negative regulator of oligodendrocyte differentiation and myelination, results in accelerated remyelination, preventing axonal loss and improving functional recovery. Together our findings demonstrate that accelerated remyelination supports axonal integrity and neuronal function after inflammatory demyelination.
A few of years ago the Chan Lab in California invented an amazing screening system to look for agents that can promote myelination and they came up with a number of targets and drugs that could promote quicker remyelination in chemical demyelination models. They were then off to do a trial with their lead drug which was Clemastine. This trial was being done in optic neuritis.
Whilst we are waiting to see the results (claimed to be mildly positive) published. Here is more animal work reporting that clamestine can promote remyelination.
However, if we read the abstract I have to say who reviews this stuff as I am sorry to say it is hardly unclear whether remyelination can prevent axonal loss as claimed.
There are masses and masses of papers showing that if you have demyelination and notably dysmyelination, then with time, nerve damage occurs!
However, the next point about the use of EAE to show remyelination independent of effects of effects on inflammation is a fair one because if you have inflammation that promotes demyelination and you remove the inflammatory signal you will get some natural repair at least early on.
In this study they use a genetic deletion of the M1 muscarinic receptor, which is targeted by clesmastine.
In this study they look at EAE see nerve loss as a consequence of the the EAE (g verses h) and see sparse demyelination indicating that MOG EAE is not a particularly good model to study remyelination after the clinical attack.
I totatlly agree but how many papers have we seen where it is claimed that treatment X or Y is good at remyelination….Loads
They then started treating EAE with clemastine and found an inhibitory effect and could not see a difference in infiltrates but concluded they they could not dissociate whether there was some effect on the inflammation.
I’m liking this caution. How many times do we see such a small drop in neurological score and it is claimed to be neuroprotection and/or repair?
As expected as there is less accumulation of disability there is less nerve loss.
Clemastine and benzatropine are two potent myelin regenerative compounds that act to antagonize six overlapping targets, including the five muscarinic acetylcholine receptor subtypes (Chrm1-Chrm5) and the histamine receptor 1 (Hrh1).
Clemastine or benzatropine induced an approximate five-fold increase in the number of oligodendrocytes and a simultaneous decrease in the number of Oligodendrocyte precurosr cells and worked out that it was Chrm1 that was mediating the effect
In this study they genetically target oligodendrocyte precurosor cells using an inducible (with taxoifen) conditional M1 muscarinic receptor knockout to stop oligodendrocyte differentiation.
They showed that remyelination would be accelerated in Chrm1 knockout mice in chemical induced demyelination and then looked in EAE and conditional deleted mice develop less clinical disease and accumulated less nerve loss.
They reported enhanced remyelination, but I like it that they say that they cannot exclude the possibility that deletion of Chrm1 from OPCs may alter a yet unidentified inflammatory role by OPCs to create well balanced view as the clinical profile suggests that this is a possibility.
However at the end of the day the results in MS are what we want to know.