Neurodegeneration in multiple sclerosis: The role of oxidative stress and excitotoxicity

In multiple sclerosis (MS) disability results from neuronal and axonal loss, the hallmark of neurodegenerative diseases (ND). Neurodegeneration is initiated by microglia activation and mediated by oxidative stress and excitotoxicity. The same sequence of events has been consistently observed in MS. However, microglia activation correlates with a marked cell infiltration in MS but not in ND. In both pathological states, peroxynitrite is the common initiating factor of oxidative stress and excitotoxicity and is thus a potential interesting therapeutic target. Oxidative stress leads to multiple lipid and protein damages via peroxidation and nitration processes. The pathomechanisms of excitotoxicity are complex involving glutamate overload, ionic channel dysfunction, calcium overload, mitochondriopathy, proteolytic enzyme production and activation of apoptotic pathways. The inflammatory component in MS is important for the design of therapeutic strategies. Inflammation not only causes axonal and neuronal loss but it also initiates the degenerative cascade in the early stage of MS. Potent anti-inflammatory agents are now available and it is not unreasonable to think that an early blockade of inflammatory processes might also block associated degenerative mechanisms and delay disability progression. The development of neuroprotective drugs is more problematic. Indeed, given the multiple and parallel mechanisms involved in neurodegeneration, modulation of a single specific pathway will likely yield a partial benefit if any.