In clinical practice, two general types of acute cerebral ischemia can be distinguished: a focal and a global cerebral ischemia. Global cerebral ischemia is a result of cardiac arrest (i.e., following a collapse of the circulation) and leads to diffuse hypoxic brain damage. This is caused by various mechanisms that will not be discussed here. Disturbances in a supply area of a cerebral artery lead to focal perfusion deficits followed by an abrupt or ictal onset of focal or global neurologic symptoms, which can be permanent or reversible.
Clinically, a variety of symptoms may become overt that can be attributed to particular anatomical areas affected by the disrupted blood flow. The cardinal symptom arising from a stroke is a hemisparesis. In conjunction with additional neuropsychological deficits, the affected hemisphere can be identified; if associated with cranial nerve dysfunction, crossed symptoms, or an initial lack of consciousness, then a vertebrobasilar locus can be diagnosed. Lacunar infarcts often lead to monosymptomatic, minor strokes.
Focal ischemia is the term applied to the pattern of damage caused by a stroke resulting from a brain infarct (Fig. 1). Here, it is important to distinguish between the seriously affected core of damage and the less severely damaged penumbra on the borders. Even within the core of the affected area, a small degree of blood flow remains (<10 ml/100 g/min). This is not enough to supply the tissue with the necessary minimum of oxygen and glucose. In turn, this means that the cells will become necrotic within 1 hr. The ischemic peripheral penumbra is defined by a rate of a b
perfusion of about 10-25 ml/100 g/min. This constitutes more than the minimum required to maintain tissue metabolism in the short term. However, it is not enough to maintain neuronal function in the long term. The period during which the cells will tolerate an ischemia (i.e., those that make up the penumbra) depends on the extent of the ischemia, just as the extent of the ischemia depends on the number of surviving cells. If this critical period becomes too long or the blood flow decreases below the minimum, the consequence is an infarct. The temporal dependence of the infarct gives rise to the concept of a therapeutic window for clinical regimens (thrombolysis and drug treatment).
At the cellular level, the energy deficit abolishes the sodium/calcium exchange at the membrane and thus leads to an increase in the intracellular sodium levels. Similarly, the energy deficit also impairs glutamate uptake inhibition that naturally leads to excessive levels of extracellular glutamate. Glutamate activates NMDA binding sites, stimulating the flow of calcium into the cell. At the same time, glutamate activates the metabotropic binding sites, leading to the outflow of calcium from intracellular stores. The resultant major increase in intracellular calcium is a central aspect of the cell destruction in ischemia. The high calcium levels activate a series of protein kinases (including protein kinase C) leading to the phosphorylation of cell proteins. Via protease activation (e.g., endonuclease), proteolysis results in the breakup of the DNA and through activation of phospholipases the breakup of lipids. This lipolysis also results in an increase in platelet activating factor and arachidonic acid, which promote the formation of free oxygen radicals. These free radicals interact with a host of related molecules, destroying these and causing more lipolysis. Reperfusion of the tissue brings a supply of oxygen that only serves to increase the formation of more radicals and can cause secondary reperfusion damage.
In the absence of oxygen, glucose is metabolized to lactate. This sets many protons free, leading to a marked acidosis that is neurotoxic and, though inducing vasodilation and reducing the density of NMDA receptors, neuroprotective.
At the level of microcirculation, protective and destructive mechanisms appear. On the one hand, vasodilation results from various neurogenic and metabolic influences. This can improve the remaining blood flow through the ischemic tissue. On the other hand, this increased perfusion is inhibited by a swelling of perivascular cells and endothelia, platelet aggregation, and leukocyte adhesion.
This juxtaposition of factors promoting repair and cell damage provides insight into why one attempts to reduce the damage resulting from a brain infarct by interfering with these circular processes.
Another route to initiate cell death following cerebral ischemia is by so-called "apoptosis." Apop-tosis is the genetically regulated form of cell death. It enables the balance between growth and elimination of cells and occurs physiologically during the embryonal development or involution processes. It seems likely that all cells have evolved the capability to undergo apoptosis and that alterations in the environmental conditions can initiate, accelerate, or slow down the process. However, dysregulation of apoptosis can also result in inflammatory, malignant, autoimmune, or neurodegenerative diseases. Furthermore, infectious agents and other cell-damaging circumstances (e.g., traumatic or ischemic conditions) can lead to apoptosis.
Apoptosis takes place in four consecutive stages: stimulation, intracellular response, apoptosis, and phagocytosis. Stimulation is mediated by many different mechanisms that are either receptor mediated or directly act on the cell. Receptor-mediated apoptosis has been demonstrated for several growth factors [transforming growth factor-b and cytokines including tumor necrosis factor (TNF)] acting via a large family of receptors on the surface of target cells (TNF receptor superfamily). Non-receptor-mediated stimuli promoting apoptosis penetrate the cell directly. They include heat shock/stress factors, free radicals, ultraviolet radiation, toxins, numerous drugs, synthetic peptides, and lymphocyte enzymes. Both types of stimuli induce the intracellular response consisting of direct activation of caspases or via the mitochondrial release of cytochrome c, which is also influenced by proapoptotic and antiapoptotic mediators.
Activated caspases are cystein proteinases that form an intracellular proteolytic cascade modulating many cellular events in the apoptotic pathway, including activation of transcription factors and induction of apoptosis-related genes. In the next step of apoptosis, intracellular calcium is released accompanied by a depletion of ATP, degradation of DNA, expression of cell surface phagocyte recognition molecules, and cell dismantling. The last step consists of phagocytic recognition of apoptotic bodies and phagocytosis of the apoptotic cells by phagocytes.
The apoptotic program is not just executed in cases of cell damage; it occurs in cases of missing growth factors and inadequate stimulation of growth. Therefore, apoptosis is also a physiological safety tool eliminating cells with deregulated growth.
In therapeutic approaches the modulation of apop-totic cell death enables new ways to treat disease. Possible mechanisms are induction of apoptosis in malignant cells, prevention of apoptosis in senescence or neurodegenerative disorders, or regulation of tissue regeneration/repair by inducing apoptosis to limit fibroblast activity and scar formation.
Four principles that are important for determining therapy may be derived from the basis of the patho-physiologic precursors described previously: reperfusion, the influence of the blood clotting system, improvement of global cerebral perfusion, and neuroprotection. Substances administered to improve neuroprotection should prolong the tolerance to ischemia in the functionally disturbed neurons and glia.
Alternatively they should protect these cells against toxic metabolites (e.g., free radicals) and excitatory amino acids (excitotoxicity). To date, animal experimentation has provided numerous impressive results that unfortunately cannot be transferred to the clinical situation. Many substances are being tested in clinical trials, whereby the next step must consider the possible combination of these substances with forms of therapy designed to promote revascularization.
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