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Neuroprotective Therapies for Multiple Sclerosis

Published Online: June 27th 2012 European Neurological Review, 2012;7(3):189-195 DOI: http://doi.org/10.17925/ENR.2012.07.03.189
Authors: Beatriz Moreno, Pablo Villoslada
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Abstract:
Overview

Multiple sclerosis (MS) is considered to be an autoimmune disease that is caused by the immune system attacking the central nervous system (CNS) leading to myelin loss and axonal damage, resulting in long-term disability. The pathophysiology of MS is complex with involvement of genetic and environmental factors that define the susceptibility to generate the autoimmune attack. In the last decade, several immunomodulatory drugs have been approved, including recombinant proteins such as interferon-beta, monoclonal antibodies such as natalizumab, or small chemicals including glatiramer acetate. In addition, there is a wide pipeline of new immunomodulators finishing Phase II or III trials. However, at present there are no approved treatments that directly reduce nervous system damage or enhance its repair. Novel neuroprotective agents have been identified in pre-clinical studies but their development is being prevented by the absence of appropriate understanding of the mechanisms of CNS damage by inflammation as well as by the lack of clinical platforms to test them. In this review, we describe the different mechanisms of axonal injury and discuss some of the principal therapeutic candidates that could provide neuroprotection in MS.

Keywords

Multiple sclerosis, therapy, neuroprotection, regenerative therapies, neuroinflammation, neurodegeneration, demyelination, remyelination, axonal damage

Article:

Multiple sclerosis (MS) is not only an inflammatory demyelinating disease as classically described but also a neurodegenerative disease with significant axonal loss, affecting all regions of the central nervous system (CNS). MS patients show significant axonal loss and to less extent neuronal loss in the grey matter, as well as multi-focal demyelination, oligodendrocyte loss and grey and white atrophy.1,2 Current immunomodulatory therapies mainly treat the inflammatory component of the disease, however they may partially confer indirect neuroprotection due to prevention of the inflammatory damage that can produce degenerative changes in the long-term. Axonal and neuronal injury in MS occurs early in the disease course with damaged axons detected in histological specimens during the first year of diagnosis.3–6 The presence of damaged axons from the early stages of the disease has raised the current concept of axonal pathology in MS as the cumulative result of inflammatory events and emphasises the need for early neuroprotective intervention.

The term neuroprotection is not well defined, but it is understood as the activation of a number of processes essential to neuronal survival, differentiation and functioning.7 A neuroprotective therapy is the one with a beneficial effect in preserving the nervous system tissue and function against neurodegenerative diseases or brain injury. This effect may take the form of protecting neurons from apoptosis or degeneration and must not only target the pathogenic mechanism inducing tissue damage (e.g. restoring blood flow in stroke or preventing inflammation in MS). In the case of MS and considering that immunomodulation has achieved a significant control of the autoimmune process, now the current challenge is the development of neuroprotective and regenerative therapies8. This is critical for several reasons. First, immunomodulatory drugs may induce significant side effects, which are related with the level of immunomodulation achieved, limiting its dosage and therefore, its efficacy. For this reason, it is highly probable that some degree of residual inflammatory activity would remains, inducing tissue damage (immunopathology). Second, current immunomodulatory drugs target mainly the activity of the adaptive immune system, without preventing to significant extent the pro-inflammatory activity of resident microglia. Chronic microglia activation is present in all stages of the disease and it has been associated with axonal damage.9,10 For both reasons, in the near future is highly likely that even in presence of a good battery of highly efficacious immunomodulatory drugs, a certain degree of chronic inflammation within the CNS will remain, requiring neuroprotective strategies. Moreover, although a significant proportion of axonal and myelin loss is due to the acute inflammatory damage, imaging and pathological studies have shown that brain atrophy and axonal loss progress along time, indicating the presence of degenerative process.11,12

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Disclosure

Beatriz Moreno and Pablo Villoslada hold patent rights for the use of Methylthioadenosine and Neurotrophin agonists for treating multiple sclerosis and other neurological diseases. Pablo Villoslada has received consultancy fees from Roche, Novartis, Digna Biotech and Neurotech, and is founder and holds stock in Bionure Farma.

Correspondence

Beatriz Moreno, Centre of Neuroimmunology, Hospital Clinic of Barcelona, Villarroel 170, 08036, Barcelona, Spain. E: bmoreno@clinic.ub.es

Received

2013-07-24T00:00:00

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