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A leading cause of adult neurologic disability in the western world, multiple sclerosis (MS) is an autoimmune disorder of unknown aetiology that results in the chronic, inflammatory, multifocal demyelination of the CNS. The heterogenous course of MS starts with an early inflammatory relapsing-remitting phase, before progressing into a degenerative stage associated with scar formation and axon loss. Oligodendrocytes are the principal cells involved in CNS myelination and therefore become prime pathological targets in MS, although axonal loss can remain clinically silent for years. In early MS, oligodendropathies are thought to be caused primarily by B cell and T lymphocyte-mediated attack on neuronal antigens whilst axonal degeneration in chronic MS is thought to be induced by intraxonal Ca2+ overload due to compensatory redistribution of Na+ channels. At present, anti-inflammatory therapies have shown poor efficacy in late MS, suggesting that mechanisms independent of inflammation may be responsible for the continued axonal degeneration in chronic MS. Current research investigating alternative therapies in chronic MS, have considered blockade of Na+ channels to reduce Ca2+ toxicity and increasing expression of neuroprotective growth factors. The more promising findings have identified LINGO-1 as a negative regulator of both myelination and oligodrendrocyte precursor cell (OPC) differentiation which suggests use of LINGO-1 inhibitors in facilitating CNS preservation in MS; a notion that is currently undergoing phase II trial investigation. Despite some promising findings, further research into the mechanisms of axonal injury and their clinical relevance in MS is still recommended in order to develop successful neuroprotective therapies in future.