Glial cell death during ischaemia

The cells located within the infarction core region rapidly undergo an anoxic depolarization; as a result neurones cease to be electrically excitable and lose their ability to maintain transmembrane ion gradients. This results in a considerable Na+ and Ca2+ influx into the cells accompanied by a substantial K+ efflux, so that very

Damaged cells Infarction core

(dead cells)

Damaged cells Infarction core

(dead cells)

Glial Cells Location

Figure 10.1 Histology of focal ischaemic damage of the brain. The focal ischaemic damage (or stroke) comprises the central zone of the infarction core, where all the cells are dead and a much larger surrounding zone of penumbra, which contains partially damaged cells. The progression of the penumbra and increase of the infarction core may take several days and can be determined by propagation of death signals through astroglial syncytium

Figure 10.1 Histology of focal ischaemic damage of the brain. The focal ischaemic damage (or stroke) comprises the central zone of the infarction core, where all the cells are dead and a much larger surrounding zone of penumbra, which contains partially damaged cells. The progression of the penumbra and increase of the infarction core may take several days and can be determined by propagation of death signals through astroglial syncytium soon (within minutes) the extracellular ion concentration deteriorates severely: e.g. in the grey matter [K+]o rises to 40-80 mM, whereas [Na+]o and [Ca2+]o decline to 60 mM and 0.2-0.5 mM respectively (Figure 10.2). Massive Ca2+ influx triggers release of glutamate from neuronal terminals, which further amplifies the vicious circle by 'glutamate excitotoxicity' (Figure 10.3). Simultaneously, the extracellular milieu becomes acidic (the extracellular pH drops to 6.5). These events almost immediately kill the neurones and most likely the glial cells too. In the penumbra, the extent of cellular changes is much less pronounced - neurones lose electrical excitability, yet all the cells retain their ion homeostasis and continue to survive, although their cytosol is often acidified, they swell, and protein synthesis and general metabolism are inhibited.

Neurones and oligodendrocytes are the most vulnerable and sensitive to ischaemic shock; astrocytes are generally more resilient. The initial cell death, which follows the stroke, is associated with 'glutamate excitotoxicity'; massive release of glutamate in the core region leads to the sustained activation of neuronal NMDA receptors, which results in Ca2+ influx; simultaneously neuronal depolarization opens voltage-gated Ca2+ channels, which add to the Ca2+ entry. At the end, neurones become overloaded with Ca2+, which strains metabolic processes.

Cell Death

Figure 10.2 Mechanisms of ischaemic cell death: Ischaemic cell death is initiated by compromised energy production, which in turn triggers loss of ion homeostasis and depolarization of the injured neural cell. This depolarization leads to a massive release of glutamate, which further depolarizes the injured cells and the cells in their immediate vicinity; this induces additional glutamate release thus establishing the vicious circle of glutamate excitotoxicity. Opening of NMDA glutamate receptors and depolarization induces uncontrolled Ca2+ entry in the cytosol, which (a) compromises mitochondria and ATP production and (b) activates numerous prote-olytic enzymes and caspase-dependent cell death pathways. This results in necrotic cell death, cell disintegration and release of cellular content into the brain parenchyma, which acts as a damage signal for neighbouring neurones and glia

Figure 10.2 Mechanisms of ischaemic cell death: Ischaemic cell death is initiated by compromised energy production, which in turn triggers loss of ion homeostasis and depolarization of the injured neural cell. This depolarization leads to a massive release of glutamate, which further depolarizes the injured cells and the cells in their immediate vicinity; this induces additional glutamate release thus establishing the vicious circle of glutamate excitotoxicity. Opening of NMDA glutamate receptors and depolarization induces uncontrolled Ca2+ entry in the cytosol, which (a) compromises mitochondria and ATP production and (b) activates numerous prote-olytic enzymes and caspase-dependent cell death pathways. This results in necrotic cell death, cell disintegration and release of cellular content into the brain parenchyma, which acts as a damage signal for neighbouring neurones and glia

A substantial part of the Ca2+ is accumulated by mitochondria, which eventually depolarize. This in turn blocks ATP synthesis and opens a highly permeable mitochondrial channel known as the permeability transition pore; this process signals the demise of mitochondria and the complete disintegration of cellular homeostasis. Persistently elevated [Ca2+]j activates numerous proteolytic enzymes and initiates necrotic neuronal death (Figure 10.3).

Schwann Cell

Figure 10.3 Mechanisms of 'vicious circles' of glutamate excitotoxicity. Massive release of glutamate opens glutamate receptors, which depolarize the cellular membrane and activate voltage-gated channels that further depolarize the cell. This results in Ca2+ influx and sustained increase in cytosolic Ca2+ concentration. Cytosolic Ca2+ ions are accumulated by mitochondria; the overload of the latter Ca2+ stops ATP production, which further compromises ion homeostasis. Increase in intracellular Ca2+ triggers additional release of glutamate, which further activates glutamate receptors. Cell depolarization and energy deficit also underlie the increase in cytosolic Na+ concentration, which eventually reverses the glutamate transporter, which produces additional glutamate release. Finally sustained increase in intracellular Ca2+ activates proteolytic enzymes, endonucleases and other death pathways, which results in cell demise

Figure 10.3 Mechanisms of 'vicious circles' of glutamate excitotoxicity. Massive release of glutamate opens glutamate receptors, which depolarize the cellular membrane and activate voltage-gated channels that further depolarize the cell. This results in Ca2+ influx and sustained increase in cytosolic Ca2+ concentration. Cytosolic Ca2+ ions are accumulated by mitochondria; the overload of the latter Ca2+ stops ATP production, which further compromises ion homeostasis. Increase in intracellular Ca2+ triggers additional release of glutamate, which further activates glutamate receptors. Cell depolarization and energy deficit also underlie the increase in cytosolic Na+ concentration, which eventually reverses the glutamate transporter, which produces additional glutamate release. Finally sustained increase in intracellular Ca2+ activates proteolytic enzymes, endonucleases and other death pathways, which results in cell demise

Oligodendrocyte precursors and mature oligodendrocytes are also very sensitive to ischaemia and glutamate excitotoxicity. Even short periods of anoxia/ischaemia cause complete loss of oligodendroglial ion homeostasis, and a very substantial [Ca2+]j elevation. The overload of oligodendrocytes with Ca2+ triggers oxidative stress and mitochondrial damage, with subsequent induction of necrosis or apoptosis, depending on the intensity of the insult.

Initiation of a toxic Ca2+ load in oligodendrocytes results from activation of several neurotransmitter receptors, and particularly glutamate receptors of AMPA/kainate and (at least in some brain regions) NMDA type. Glutamate concentration around ischaemic axons can rise very rapidly; axoplasm contains ~1mM of glutamate, and the axolemma is endowed with Na+/glutamate transporters. Loss of ion homeostasis triggered by ischaemia causes acute axonal depolarization (due to [K+]o increase) and substantial elevation in axoplasmic

Na+; these changes result in reversal of the Na+/glutamate transporter and massive release of glutamate. Glutamate in turn triggers Ca2+ entry into oligo-dendroglial cells: the latter do not express the GluR2 AMPA receptor subunit (see Chapter 5.3.1), and this renders their AMPA receptors Ca2+ permeable; similarly Ca2+ also can pass through kainate receptors; recent data also indicate that at least some oligodendrocytes express NMDA receptors, which can be activated during ischaemia. Oligodendrocyte precursors, which have particularly high levels of AMPA/kainate receptor expression, appear the most vulnerable to glutamate toxicity. Interestingly, exposure to glutamate can directly destroy the myelin sheath; this involves Ca2+ influx through NMDA receptors, which are localized to myelin sheaths, whereas ionotropic AMPA receptors appear to be localized to the cell bodies and may mediate cell death. Indeed Ca2+ influx into the compact myelin affected by ischaemia has been directly demonstrated in imaging experiments; moreover antagonists to NMDA receptors prevented ischaemia-induced deterioration of myelin. Another important pathway for [Ca2+] elevation is associated with Ca2+ release from the ER store activated by depolarization of oligodendrocyte membrane, which results from acute elevation in extracellular [K+] triggered by ischaemia (depolarization-induced Ca2+ release through RyRs - see Chapter 5.4).

Astrocytes generally are less sensitive to glutamate excitotoxicity. Astroglial cultures readily survive relatively prolonged periods (up to several hours) of oxygen and/or glucose deprivation. In vivo, however, astrocyte sensitivity to ischaemic insults seems to be much higher. Many, but not all astroglial cells in hippocampus survive brief (~10min) periods of ischaemia (which is enough to kill a very significant number of neurones), yet longer cessation of blood flow causes prominent astrocytic death. White matter astrocytes seem to be even more vulnerable: astroglial cells in the optic nerve begin to die within 10 to 20 minutes after the onset of ischaemia.

Nonetheless, astroglial cells can survive for long periods of time in the penumbra. In the latter, the reduced blood flow still delivers relatively high amounts of glucose, which can be utilized by astrocytes through anaerobic glycolysis. This, however, produces lactate, which in turn promotes acidosis. Importantly, astroglia are rather sensitive to acidification of their environment: lowering of pH to ~6.6 completely inhibits astroglial ATP production and very rapidly (in about 15 minutes in vitro) kills astrocytes. Interestingly, hyperglycaemia exacerbates growth of the infarction core, most likely through intensifying anaerobic glycolysis and increasing acidosis. At the same time astrocytes are also vulnerable to reactive oxygen species (ROS), which can be produced in large quantities during reperfusion; ROS induce cell death through mitochondrial depolarization and opening of the permeability transition pore. One of the early consequences of astroglial injury is the disruption of their distal processes; the phenomenon described a century ago by Alzheimer and Ramón y Cajal as clasmatodendrosis ('fragmentation of dendrites' from the Greek 'clasmato' 'KXao^aTo' - fragment, piece broken off).

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