During early reperfusion, ATP levels and total adenylate charge recover rapidly. If the ischemic insult has been less than 20 min, the membrane ionic gradients also recover quickly. After much longer insults of 1 to 3 h, total tissue calcium loads actually increase during reperfusion. It is felt that this reflects extensive and irreversible cell membrane injury during these very prolonged periods of ischemia.
Arachidonate is rapidly oxidized by both cyclooxygenase and lipoxygenase, and returns to preischemic levels within 30 min of reperfusion. Several vasoactive substances are produced by the metabolism of arachidonate. The prostaglandins are the products of cyclooxygenase, and the leukotrienes are the products of lipoxygenase. The production of the vasodilatory prostaglandin prostacyclin is severely inhibited during early reperfusion. Thus, vasospastic compounds predominate in the leukotriene and prostaglandin products. While the free arachidonic acid levels rapidly return to baseline during reperfusion, leukotrienes remain markedly elevated for at least 24 h. The time course of leukotriene elevation may explain the alterations in blood flow seen in the postischemic brain (the "no-reflow" phenomenon). Restoration of normal or mildly hypertensive systemic arterial pressure produces an initial brain hyperperfusion. However, within 1 h, global brain perfusion has dropped to levels of 20 to 40 percent of normal, where it remains for up to 1 to 2 days. This phenomenon occurs without a change in intracranial pressure and was originally thought to lead to failure of high-energy metabolism and neuronal death during reperfusion. However, therapy that inhibited postischemic brain hypoperfusion had little effect on neurologic outcome.
Membrane lipids are extensively peroxidized by iron-dependent radical reactions during reperfusion. Within the first 30 s of reperfusion, there is a brief burst of oxygen-based free radical production, although the precise identity of the radical species remains unknown. Xanthine oxidase and cyclooxygenase, whose substrates are hypoxanthine and arachidonate respectively, produce O 2- as a side product. Availability of a transition metal, such as iron, is required for reaction of oxygen radicals with tissue macromolecules, including lipids (lipid peroxidation). The brain glia have abundant stores of oxidized (ferric) iron, mostly in ferritin and transferrin, forms in which the iron is unable to act as a catalyst for oxygen radical reactions. However, O 2-, which is present in excessive amounts during early reperfusion, promotes reduction of ferric iron and release of ferrous iron from ferritin, and lipid peroxidation in the reperfused brain has been demonstrated by many laboratories and maps to selectively vulnerable neurons. These reactions also appear to be involved in the genesis of the postischemic hypoperfusion phenomenon, which is inhibited by superoxide dismutase and deferoxamine or U74006F, a lipid peroxidation chain terminator.
Excitatory amino acid neurotransmitters appear to play a role in the injury produced by focal brain ischemia such as stroke; it is unclear whether the same holds true in global brain ischemia. However, excitatory neurotransmitter uptake is inhibited by arachidonate and products of lipid peroxidation, and thus continued stimulation of receptors may contribute to neuronal damage by as yet unidentified mechanisms.
Protein synthesis is suppressed during ischemia by lack of ATP.8 However, even with the rapid restoration of ATP levels that accompanies reperfusion, there is a severe suppression of protein synthesis that varies with duration of ischemia, brain region, and individual proteins. Whereas most regions of the brain recover their ability to synthesize protein following a short ischemic period, protein synthesis in the selectively vulnerable regions is depressed by about 90 percent early in reperfusion and does not recover significantly. Failure of protein synthesis is due to a disruption in the formation of new ribosomal translation complexes. Initiation, the rate-limiting step in translation, requires the coordinated assembly of the ribosomal subunits, the mRNA to be translated, and the amino-acyl tRNA for the first amino acid (always methionine in eukaryotes). This process is orchestrated by a family of proteins named eukaryotic initiation factors (eIFs). The eIF4 and eIF2 complexes are the major regulatory points for translation initiation. Cellular mRNAs vary greatly in their binding efficiency to eIF4E, and under normal physiologic situations message selection for translation initiation is modulated by altering the phosphorylation of Ser 209 on eIF4E. However, under conditions of cellular stress (e.g., heat shock, viral infection, or starvation), rates of global protein synthesis are downregulated by phosphorylating Ser 51 on the a subunit of eIF2 [eIF2a(P)].
Studies have now identified three important changes in eIFs that occur during brain ischemia and reperfusion: (1) a modest degree of proteolytic degradation of eIF4E occurs during ischemia, but without change in its phosphorylation state during either ischemia or reperfusion; 91° (2) there is substantial proteolytic degradation of eIF4G mediated by calpain during both ischemia and reperfusion;1 l.2 and (3) probably most important, there is an approximately twentyfold increase in eIF2a(P) during early reperfusion. In nonischemic tissue, phosphorylated eIF2a is found exclusively in astrocytes. 13 After only 10 min postischemic reperfusion, there is prominent eIF2a(P) immunostaining in the cytoplasm of neurons in both the hippocampus and cortex. After 1 h of reperfusion, eIF2a(P) is prominent in both the nuclei and cytoplasm of selectively vulnerable neurons in both the hippocampus and cortex; nuclear eIF2a(P) is never seen in ischemia-resistant neurons. By 4 h reperfusion, the pattern of nuclear eIF2a(P) immunostaining in vulnerable neurons suggests nuclear condensation consistent with the early stages of apoptosis. These results provide a mechanism for the inhibition of protein synthesis in vulnerable neurons during reperfusion and, together with other evidence suggesting a role for eIF2a(P) in causing apoptosis, may represent a fundamental phenomenon in the causal pathway leading to the death of vulnerable neurons. It is interesting to note that animals treated with 20 U/kg insulin at resuscitation are able to dephosphorylate eIF2a(P) and recover protein synthesis in vulnerable hippocampal neurons by 90 min reperfusion. Thus, growth factors, including fibroblast growth factor, nerve growth factor, insulin-like growth factor 1, and insulin, all of which have been shown to improve neuronal survival in the laboratory, may have a role in limiting and repairing neuronal damage. 6
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