Excitotoxicity and motor neurone disease: a review of the evidence

Excitotoxic mechanisms have a well established role in the pathogenesis of neuronal injury following acute CNS insults such as ischaemia and trauma. Their role in the selective cell death which occurs in chronic neurodegenerative disorders such as motor neurone disease (MND) is more speculative. The traditional classification of glutamate receptor subtypes which mediate excitotoxicity requires modification in the light of new molecular data. There is much greater structural and functional diversity in this receptor family than previously envisaged and it is quite possible that specific populations of neurones will be characterised by a unique profile of glutamate receptor subtypes which may be a factor determining their selective vulnerability. The molecular mechanisms underlying excitotoxic neuronal injury are still being elucidated but it is clear that the cascade of events resulting from elevation of intracellular free calcium is likely to play a major role. As well as being a primary mechanism of neuronal injury, excitotoxicity can secondarily damage neurones whose energy metabolism is impaired from some primary pathological process. The 8 lines of evidence that primary or secondary excitotoxic mechanisms may be involved in the selective neuronal injury of MND are discussed. The evidence, while still circumstantial, is sufficient to warrant further research effort in this field, not least because the emergence of pharmacological agents which modify specific aspects of excitatory amino acid neurotransmission offer the possibility of therapeutic intervention in MND.