The remyelination dogma

The myelin sheath is a major component of the white matter of the vertebrate brain and spinal cord.  It serves as an electrical insulator along nerve axons that accelerates conduction and enables higher brain function [1].  This specialised lipid-rich structure maintains axonal integrity by providing metabolic and trophic support, whilst allowing for efficient nerve conduction by minimising energy consumption [1].  However, characteristic to a number of CNS disease states is the process of demyelination [2].  For example, in Multiple Sclerosis (MS), where white and grey matter brain lesions occur throughout the brain and spinal cord, there is defective saltatory signal conduction and axonal damage, which then manifests itself in clinical symptoms such as motor weakness [3].  Interestingly though, in the adult CNS a quiescent pool of precursor cells exists which can differentiate into new oligodendrocytes capable of replacing lost myelin sheath [4].  In fact remyelination is a natural repair mechanism believed to protect against progressive axonal damage in MS.  Therefore, the focus of current therapeutic research has recently shifted from preventative to reparative in respect to existing white matter lesions.

The beneficial effects of remyelination are functional recovery via the restoration of both axonal conduction and trophic axonal support [5], and the additional neuroprotective properties of reducing the cell’s energy consumption.  This is done via recruitment of resident precursor cells to generate new oligodendrocytes [6].  However, the extent of this regeneration is limited. Although in vivo models to study MS show efficient and extensive remyelination, myelin sheaths generated in the adult brain of MS patients are generally thinner with shorter internodes. In MS, the process of remyelination is insufficient in about 80% of lesions and fails to counteract the accumulation of permanent axonal damage [7].  Successful remyelination may require the existence of oligodendrocytes, but initially needs the necessary factors that allow for the sufficient migration and differentiation of these precursor cells [8].  It is these factors that are thought to limit its success in the MS brain, although the underlying cellular and molecular mechanisms remain poorly understood.

But even so, do therapies focusing on enhancing this remyelination process inevitably incur neuroprotection?  One example which suggests they may not be so intimately related is the drug Fingolimod, approved by the FDA in 2010 to treat relapsing-remitting MS (RRMS).  Although this drug has been shown to reduce brain atrophy in RRMS patients [9], The Lancet this year reported that the INFORMS study, which used this drug in primary-progressive MS (PPMS) patients, failed to show any improvement in the neurodegenerative process [10].  So, why are we failing to find treatment for PPMS?  Is remyelination really the answer?  There is evidence from animal studies which shows that remyelination and neuroprotection may actually occur independently of each other.  After completion of remyelination the mice showed initial recovery of locomotor performance; however 6 months post completion, performance then began to decline compared to age-matched controls [11].  These studies highlighted that axonal damage continues long after remyelination, and can still accumulate over time to result in functional impairment.  Remyelination alone cannot compensate for the stress that demyelination has on a neuronal cell, and therefore neuroprotective strategies that do not rely solely on restoration of myelin must be explored.

Translating both remyelinating and neuroprotective strategies from bench to bedside, however, relies on appropriate in vitro and in vivo experimental settings for the development of new drug targets.  Focusing on remyelination in MS, the most commonly used animal models are toxin models, whereby a focal injection or systemic administration of a toxin, for example lysolecithin or cuprizone respectively, induces demyelination and successive remyelination [12].  A benefit of these models is that they exhibit endogenous remyelination with a predictable spatial and temporal distribution.  However, because remyelination is certain in these models, they are unsuitable for accessing the ability of a pharmaceutical compound to induce remyelination and can only be used to study the acceleration of it.  Additionally, the lesions in these models do not develop much, if any, autoimmune reaction, and inflammation is one reason thought to be behind the failure of remyelination in the MS brain.  This may be one reason behind some of the discrepancies that are seen between lab and clinic.  Having said that, remyelination in both the lysolecithin and cuprizone model is hampered in aged animals the chronic EAE model exhibits limited remyelination and a substantial input from the immune system [12].  These paradigms may provide a way of better studying the induction of remyelination in a compromised environment.

In conclusion, two factors must be addressed for research in this are to proceed: firstly the experimental setting most appropriate to study drug targets for remyelination; and secondly, the simultaneous neuroprotective strategies that should be employed to prevent the accumulation of irreversible grey matter damage.

Blog written by Victoria Miller

 

Bibliography

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