A loss of BLOOD flow to a tissue or organ. The brain derives most of its energy from the oxidative metabolism of GLUCOSE: both glucose and OXYGEN are supplied to the brain by an extensive CEREBRAL VASCULATURE. When the blood supply is compromised, ischaemia leads to a series of events, culminating in neuronal death. Ischaemia can occur globally, usually due to cardiac arrest, or focally, for example due to the blockage of an isolated cerebral vessel, or STROKE. GLOBAL ISCHAEMIA and FOCAL ISCHAEMIA are different in both the scale of damage done, and the region in which the damage occurs. Global ischaemia due to temporary cardiac arrest is usually short-lived and fully reversible, and results in neuronal damage throughout the brain. In contrast, focal ischaemia is often long-lasting, and involves death of neurons and other cerebral tissue, such as EPITHELIAL CELLS in the cerebral capillaries, in a localized region known as the INFARCT. In addition, neuronal death is often seen spreading in a rim around the infarct, known as the penumbra, and in remote brain structures which are innervated by the region of infarct. A feature of both focal and global ischaemia is that much neuronal death occurs some time later than the initial insult. This observation suggests that mechanisms secondary to the ischaemic insult are responsible for this delayed neuronal death.
In both global and focal ischaemia, there is a hierarchy within neurons in susceptibility to ischaemic damage. Neurons most at risk from ischaemic damage are in regions of brain which have high densities of GLUTAMATE RECEPTORS, and include STRIATUM, CORTEX and HIPPOCAMPUS. Ischaemia is associated with elevated extracellular GLUTAMATE levels, and antagonists to both AMPA and NMDA receptors are found to prevent delayed neuronal death in animal models of ischaemia. This suggests that glutamate acts as an excitotoxin (see EXCITOTOXINS) in ischaemia, and that NMDA and AMPA antagonists may be useful in clinical treatment of ischaemia.
Without the supply of oxygen and glucose, neurons quickly become depleted in ADENOSINE TRIPHOSPHATE (ATP), and are unable to fuel normal cellular reactions. An immediate consequence is the loss of function of the SODIUM-POTASSIUM PUMP, an ion pump which maintains the negative membrane potential through active uptake of potassium ions and extrusion of sodium ions.
The consequent increase in extracellular potassium concentrations results in bursts of DEPOLARIZATION in neurons, followed by electrical silence. Cell depolarization leads to release of large amounts of neurotransmitter, including glutamate. Most glutamate released during normal neuronal firing is rapidly taken up by GLIAL CELLS, where it may be metabolized to GLUTAMINE, and exported to neurons for resynthesis of glutamate. During ischaemia, however, there is a lack of ATP to fuel uptake mechanisms in glial cells, and so the action of glutamate on neurons is prolonged. Activation of glutamate receptors during normal neuronal firing leads to an influx of CALCIUM ions through NMDA receptors, and some calcium-permeable AMPA receptors. Antagonists of calcium channels are protective against ischaemic damage in animal models, indicating that calcium influx in ischaemic tissue, probably through glutamate receptors, causes neuronal death. In normal cells, cytosolic calcium concentrations are tightly controlled by sequestration into ENDOPLASMIC RETICULUM and MITOCHONDRIA, through an ATP-dependent sodium-calcium pump. Small increases in cytosolic calcium concentrations affect many cellular reactions. Calcium is required for initiation of phosphatase and KINASE action, regulating the activity of cellular enzymes, receptors, SECOND MESSENGERS and GENE expression. Other enzymes which act to break down cell components are also calcium-dependent. For example, increases in calcium concentration result in stimulation of proteases, which break down proteins, and ENDONUCLEASES, which mediate the breakdown of DNA and RNA, the genetic material of the cell. Calcium also stimulates the production of FREE RADICALS, including production of NITRIC OXIDE through stimulation of nitric oxide synthase. Free radicals, being highly reactive, are potentially destructive, and can mediate breakdown of membranes and nuclear material. All of these mechanisms may be initiated by prolonged exposure of a neuron to high extracellular glutamate levels during ischaemia, and each may over a duration lead to the death of the cell, through disruption of its enzymatic processes, loss of control of gene expression, and breakdown of PROTEINS, membranes and genetic material, vital for survival of the cell.
The consequences of cerebral ischaemia may be death, or severe cognitive impairment, the exact symptoms of which vary depending on the location of the ischaemic damage. Thus, the observation that most neuronal death occurs hours after the initial insult is important in treating patients with ischaemia. This delay may represent a window of opportunity, often referred to as the therapeutic window during which drugs such as glutamate antagonists may be used to prevent delayed neuronal death as a result of ischaemia.
FIONA M.INGLIS
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