BIOCHEMICAL-CHANGES ASSOCIATED WITH SELECTIVE NEURONAL DEATH FOLLOWING SHORT-TERM CEREBRAL-ISCHEMIA

A brief interruption of blood flow to the brain results in the selecti ve loss of specific subpopulations of neurons. Important advances have been made in recent years in defining the biochemical changes associa ted with cerebral ischaemia and reperfusion and in identifying physica l and chemical interventions capable of modifying the extent of neuron al loss. Neuronal death is not irreversibly determined by the ischaemi c period but develops during recirculation over a period of hours or e ven days in different susceptible neuronal populations. The onset of i schaemia produces a rapid decline in ATP production and an associated major redistribution of ions across the plasma membrane including a la rge intracellular accumulation of Ca2+ in many neurons. Alterations su bsequently develop in many other metabolites. These include a marked a nd progressive release of neurotransmitters and a rapid accumulation o f free fatty acids. Most of these alterations are reversed within the first 20 min to 1 hr of recirculation. The changes essential for initi ating damage in neurons destined to die have not been definitively ide ntified although there is some evidence suggesting roles for the intra cellular Ca2+ accumulation, the release of the neurotransmitter glutam ate and a brief burst of free radical production which occurs during e arly recirculation. During further recirculation, there are reductions in oxidative glucose metabolism and protein synthesis in many brain r egions. Pew changes have been detected which distinguish tissue contai ning ischaemia-susceptible neurons from ischaemia-resistant regions un til 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 affec ting ischaemia-susceptible regions which could contribute to neuronal loss. The mitochondrial change may be one indicator of a slowly develo ping post-ischaemic increase in susceptibility to oxidative damage in some cells.