Excitotoxicity has been implicated as a key pathogenic pathway in a number of neurodegenerative diseases and conditions including Alzheimer’s disease, amyotrophic lateral sclerosis, multiple sclerosis, brain trauma, and stroke. While acute excitotoxicity can result in the initiation of cell death pathways, chronic or low levels of excitotoxin exposure may result in a more slowly progressing pathological cascade. In this respect, there is emerging evidence that excitotoxicity can result in axonal degeneration and pathology, a key
pathological feature of many of these neurodegenerative conditions. Recent evidence supports the notion that axon degeneration can be a separate and independent process from cell death, and thus mechanisms involved need to be understood in order to provide axonal protection in neurological disease. While axon degeneration following transection (Wallerian degeneration) has been well documented, less is known about axon degeneration following other insults such as excitotoxicity and the mechanistic relationships they bear to
Wallerian degeneration. In particular, how a primarily somatodendritic insult, such as excitotoxicity, results in a pathological cascade within the axon is unclear. This chapter reviews our current understanding of the pathologicalchanges and mechanisms of excitotoxin-induced axon degeneration with particular reference to our understanding of other forms of axonal degeneration and potential mechanisms involved. An increased understanding of the mechanisms of axon degeneration in neurological disease is essential to the development of therapeutic agents targeting axon protection.