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
To view the full article in PDF or eBook formats, please click on the icons above.