Astrocytes, however, may act not only as protectors of the brain; in certain conditions (especially upon severe insults) astroglial cells may exacerbate the cell damage, contributing to several vicious circles triggered by the stroke. First of all, the astroglial involvement in controlling brain glutamate concentration is double edged. The ability of astrocytes to remove glutamate from the extracellular space leads to glutamate accumulation in their cytosol in very high concentrations (up to 10 mM). Upon severe hypoxic/hypoglycaemic conditions astroglial cells may turn from being the sink for glutamate to being the main source of the latter. Astrocytes can release glutamate by several mechanisms (see Chapter 5.6) which are triggered in ischaemia: (1) reversal of glutamate transporters can be caused by ATP depletion accompanied with an increase in intracellular Na+ concentration and cell depolarization; (2) elevation of [Ca2+]j in astrocytes, which follows the ischaemic insult, may trigger the release of glutamate stored in vesicles; (3) acidosis and lowering of extracellular Ca2+ concentration can open glutamate-permeable hemichannels; (4) ATP released in high concentrations by dying and disintegrating neurones can open astroglial P2X7 purinoreceptors, which also allow glutamate release; and (5) brain oedema can activate volume-sensitive channels, which also allow passage of glutamate.
The second important pathological role of astrocytes is associated with a progression of the infarction core through the penumbra. This expansion of the death zone is a slow process, which may proceed for several days after the initial insult. It is more than likely that growth of the infarct zone into the penumbra, or alternatively containing the infarct zone within its initial borders, is a highly complex process, which involves different cellular mechanisms. The importance of the core-penumbra interactions is also obvious because this process determines the final extent of brain damage.
The slow progression of damage spread through the ischaemic penumbra implicates specific signalling processes propagating from the infarction core towards the surrounding tissue. Signalling through neuronal network can be excluded, as neuronal excitability is lost after even a mild reduction of cerebral blood flow. The alternative route for propagation of death signals may involve the astroglial syncytium. This scenario begins with the generation of aberrant [Ca2+]j waves in an astrocyte which may in turn evoke the distant release of glutamate from astrocytes beyond the ischaemic focus. Thus, a propagating wave of glutamate release from astrocytes can contribute to the extension of infarction (Figure 10.5).
The second route for infarction expansion is associated with spreading depression, which often occurs in the penumbra (Chapter 10.2). The spreading depression waves originate at the very border between the necrotic core and the ischaemic penumbra, and these waves are initiated by high extracellular K+ concentration present around the core. The spreading depression wave occurs as often as every 10-15 minutes, which is determined by the refractory period of the cells in the penumbra. There is a fundamental difference between spreading depression in normal brain tissue and in the compromised ischaemic penumbra. The cells in penumbra retain their ion homeostasis, and therefore each wave of spreading
Figure 10.5 Astrocytes may exacerbate infarction progression through the penumbra by propagating Ca2+ waves or by propagating 'death signals'. Death signals may travel through the astroglial syncytium, triggering injury to cells distant to the site of the infarction. See the text for detailed explanation
Figure 10.5 Astrocytes may exacerbate infarction progression through the penumbra by propagating Ca2+ waves or by propagating 'death signals'. Death signals may travel through the astroglial syncytium, triggering injury to cells distant to the site of the infarction. See the text for detailed explanation depression results in further imbalance between the energy requirement of the depolarized tissue and the energy supply; this imbalance leads to cell death. As a result, there is a direct correlation between the number of spreading depression waves and the spread of necrotic area into the penumbra. Metabolic imbalance also determines the longer duration and longer recovery of spreading depression in ischaemic penumbra. The spreading depression waves propagate from the ischaemic region to the healthy tissue, causing some functional disturbances, although this does not result in any cell death outside the borders of ischaemic tissue.
The extension of the necrotic zone through the penumbra may demarcate the primary extension of astroglial failure, which in turn depends on a variety of factors. For example, the extent of the circulation breakdown would determine the relative activity of glycolysis, and hence production of lactate and accumulation of protons in the extracellular space. Profound extracellular acidification will in turn induce astrocytic collapse. This process can be further exacerbated by accumulation of extracellular K+ ions and subsequent depolarization, accompanying for example the wave of spreading depression. At the same time release of glutamate by astrocytes in the penumbra can kill neighbouring neurones and produce even further accumulation of K+ and secondary release of glutamate and ATP. At the same time increases in [K+]o would initiate astroglial swelling, which will reduce the extracellular space, hence further increasing concentrations of K+ and glutamate in the latter, and further obstructing circulation. In other words, the very same mechanisms that protect neurones during ischaemic stress, may also participate in extending the damage; this happens when the astroglial capacity for survival in ischaemic conditions is exhausted, which in turn activates several vicious positive feedback loops, that result in cell death and in extension of the necrotic zone through ischaemic penumbra. All in all, the stroke should never be considered as a primary neuronal disease, as indeed the outcome of focal brain ischaemia is directly determined by astroglial performance.
Was this article helpful?