Metabolic injury to axons and myelin

CNS white matter, the collection of axons and supporting glia of the mammalian CNS, makes up close to 50% of the human brain by volume. Interruption of vital interconnects within this tissue, even over a short segment, often leads to serious morbidity in a broad range of neurological disorders. Axons, glia and myelin express a complex array of conventional voltage gated ion channels, intracellular Ca(2+) release channels, neurotransmitter uptake and release mechanisms, together with matching transmitter receptors. Dysregulation of ion homeostasis induced by injury or energy failure leads to depolarization and intracellular Na(+) accumulation, which in turn triggers inappropriate ion translocation (i.e. Ca(2+) influx) and transmitter release; together these events further promote more Ca(2+) influx, while at the same time triggering even more toxic Ca(2+) release from intracellular Ca(2+) stores. Uncontrolled intracellular Ca(2+) increases overactivate a variety of Ca(2+)-sensitive enzyme systems culminating in permanent injury to axon, myelin and glia.