The link of inflammation and neurodegeneration in progressive multiple sclerosis

Progressive multiple sclerosis (MS) is characterized clinically by the accumulation of neurological disability without unequivocal recovery. Understanding the mechanisms that determine entering in this stage of the disease is a great challenge in order to identify potential therapeutic targets. Recent advances in defining more accurately the progressive phenotype of MS, have concluded that differences between primary and secondary progressive forms of disease are relatively quantitative rather than qualitative. In both cases, a large number of molecular and cellular events that might lead to neurodegeneration have been suggested. These include microglia activation, chronic oxidative injury, accumulation of mitochondrial damage in axons, age-related disturbances and dysfunctional axonal transport among others. Commonly, these pathological mechanisms have been considered as a result of inflammatory demyelination but a primary degenerative condition has also been argued. It is now clear that both events contribute to the progression of the disease, however their temporal sequence is still a matter of debate. A detailed knowledge of progressive MS pathogenesis will allow to develop effective treatments for both progression and symptom management that should be based on a combination of anti-inflammatory, regenerative and neuroprotective strategies. In this review, we summarize current data and recent hypothesis about pathological forces that drive progression of damage in MS, i.e. cumulative cortical demyelination and neurodegeneration as well as diffuse alterations (microglia activation, axonal injury and atrophy) throughout white and grey matter in the brain and spinal cord. Finally, we discuss the potential of the aforementioned proposed disease mechanisms with regard to developing suitable therapies to halt the progression in MS pathology.