Another remyelination candidate effective in animals

A
Lundgaard I, Luzhynskaya A, Stockley JH, Wang Z, Evans KA, Swire M, Volbracht K, Gautier HO, Franklin RJ, Ffrench-Constant C, Attwell D, Káradóttir RT. Neuregulin and BDNF Induce a Switch to NMDA Receptor-Dependent Myelination by Oligodendrocytes. PLoS Biol. 2013 Dec;11(12):e1001743. Epub 2013 Dec 31.

Myelination is essential for rapid impulse conduction in the CNS, but what determines whether an individual axon becomes myelinated remains unknown. Here we show, using a myelinating coculture system, that there are two distinct modes of myelination, one that is independent of neuronal activity and glutamate release and another that depends on neuronal action potentials releasing glutamate to activate NMDA receptors on oligodendrocyte lineage cells. Neuregulin switches oligodendrocytes from the activity-independent to the activity-dependent mode of myelination by increasing NMDA receptor currents in oligodendrocyte lineage cells 6-fold. With neuregulin present myelination is accelerated and increased, and NMDA receptor block reduces myelination to far below its level without neuregulin. Thus, a neuregulin-controlled switch enhances the myelination of active axons. In vivo, we demonstrate that remyelination after white matter damage is NMDA receptor-dependent. These data resolve controversies over the signalling regulating myelination and suggest novel roles for neuregulin in schizophrenia and in remyelination after white matter damage.



Glutamate is a neurotransmitter molecule that transmits excitatory signals between nerves. It has been found that so myelin forming cells respond to this neurotransmitter. Neuroregulin is nerve developmental factor. In this study it turns oligodendrocytes into cells that can respond to the glutamate, and if they block the glutamate receptor it stops myelination, but so if you give glutamate it should be good for you. 




However , this is where biology is a spoiler because if you give glutamate you cause excitotoxicity and the nerves can die, so you have conflicting pathways and it is thought that there is too much glutamate in MS so why is there poor remyelination (if that is indeed the case) or is this why the grey matter appears to remyelinate quite happily whereas the white matter less so. So blocking the NMDA receptor stops myelination. 


Memantine is an NMDA blocker that is used to treat cognitive problems in Alzheimer’s Disease. It has been tried in MS as an anti-symptomatic treatment. It shows neuroprotective and symptom control potential in EAE and can be neuroprotective in humans also although the effect may not be great and in more than one study the cognitive impairment was made transiently worse.

Can neurregulin be used to promote remyelination. Another candidate for treatment



So these studies indicate there are conflicting pathways one promoting myelin whilst the same target can inhibit nerve function. Unfortunately this is biology and is common in remyelination, in that the targets do a lot of different things besides affecting myelin and so blocking them can be good and possibly bad….leading to side effects.

Can remyelination be kick started with a pulse of drug or does it need continuous treatment..pharma will try convince you of the latter, we need to ask for the evidence.

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MouseDoctor

2 comments

  • Mouse,

    Thanks. It looks as if there's a lot going on regarding research into remelination. However, Prof G has suggested in earlier posts that remyelination isn't an issue in MS. Does this mean that all the remyelination research and potential trials will be a waste of time?

    I was hopeful when i heard that Biogen were trialling a remyelinating therapy – antilingo. It all seems to have gone quiet. Was it unsuccessful?

    • The question is is how well does the sCNS remyelinate if anti-inflammation is successsful
      Remyelination is the default pathway.

      The answer is in the pathology.

      Anti lingo trials is ongoing hopefully enough of the antibody gets into the cns i am not sure about this and it needs to be done in a case on add on to anti inflammatory. Maybe g knows when th trials will end

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