Biochemical changes associated with selective neuronal death following short-term cerebral ischaemia.

A brief interruption of blood flow to the brain results in the selective loss of specific subpopulations of neurons. Important advances have been made in recent years in defining the biochemical changes associated with cerebral ischaemia and reperfusion and in identifying physical and chemical interventions capable of modifying the extent of neuronal loss. Neuronal death is not irreversibly determined by the ischaemic period but develops during recirculation over a period of hours or even days in different susceptible neuronal populations. The onset of ischaemia produces a rapid decline in ATP production and an associated major redistribution of ions across the plasma membrane including a large intracellular accumulation of Ca2+ in many neurons. Alterations subsequently develop in many other metabolites. These include a marked and progressive release of neurotransmitters and a rapid accumulation of free fatty acids. Most of these alterations are reversed within the first 20 min to 1 hr of recirculation. The changes essential for initiating damage in neurons destined to die have not been definitively identified although there is some evidence suggesting roles for the intracellular Ca2+ accumulation, the release of the neurotransmitter glutamate and a brief burst of free radical production which occurs during early recirculation. During further recirculation, there are reductions in oxidative glucose metabolism and protein synthesis in many brain regions. Few changes have been detected which distinguish tissue containing ischaemia-susceptible neurons from ischaemia-resistant regions until the development of advanced degeneration and neuronal loss. Subtle changes in cytoplasmic Ca2+ content and a decrease in the respiratory capacity of mitochondria are two changes apparently selectively affecting ischaemia-susceptible regions which could contribute to neuronal loss. The mitochondrial change may be one indicator of a slowly developing post-ischaemic increase in susceptibility to oxidative damage in some cells.