Elsevier

Neuropharmacology

Volume 55, Issue 3, September 2008, Pages 289-309
Neuropharmacology

Bioenergetics of cerebral ischemia: A cellular perspective

https://doi.org/10.1016/j.neuropharm.2008.05.023Get rights and content

Abstract

In cerebral ischemia survival of neurons, astrocytes, oligodendrocytes and endothelial cells is threatened during energy deprivation and/or following re-supply of oxygen and glucose. After a brief summary of characteristics of different cells types, emphasizing the dependence of all on oxidative metabolism, the bioenergetics of focal and global ischemia is discussed, distinguishing between events during energy deprivation and subsequent recovery attempt after re-circulation. Gray and white matter ischemia are described separately, and distinctions are made between mature and immature brains. Next comes a description of bioenergetics in individual cell types in culture during oxygen/glucose deprivation or exposure to metabolic inhibitors and following re-establishment of normal aerated conditions. Due to their expression of NMDA and non-NMDA receptors neurons and oligodendrocytes are exquisitely sensitive to excitotoxicity by glutamate, which reaches high extracellular concentrations in ischemic brain for several reasons, including failing astrocytic uptake. Excitotoxicity kills brain cells by energetic exhaustion (due to Na+ extrusion after channel-mediated entry) combined with mitochondrial Ca2+-mediated injury and formation of reactive oxygen species. Many (but not all) astrocytes survive energy deprivation for extended periods, but after return to aerated conditions they are vulnerable to mitochondrial damage by cytoplasmic/mitochondrial Ca2+ overload and to NAD+ deficiency. Ca2+ overload is established by reversal of Na+/Ca2+ exchangers following Na+ accumulation during Na+–K+–Cl cotransporter stimulation or pH regulation, compensating for excessive acid production. NAD+ deficiency inhibits glycolysis and eventually oxidative metabolism, secondary to poly(ADP-ribose)polymerase (PARP) activity following DNA damage. Hyperglycemia can be beneficial for neurons but increases astrocytic death due to enhanced acidosis.

Section snippets

Introduction: brain ischemia injures all brain cells

Twenty-five years ago it was shown that brain ischemia only produces edema in cerebral cortex when damage of astrocytes and endothelial cells has occurred, i.e., an infarct has been formed (or is forming), whereas neuronal necrosis alone was insufficient for edema formation (Petito et al., 1982, Plum, 1983). This was a time when the roles of non-neuronal cells in normal and abnormal function had begun to attract interest, including their reactions to ischemia (Hertz, 1981). It is now realized

Cellular composition of brain

Both neurons and non-neuronal cells are made up of subgroups, e.g., neurons releasing and/or expressing receptors for different transmitters, the glial cells astrocytes, oligodendrocytes, microglia, and NG2 cells (previously regarded as oligodendrocyte precursors, but now recognized as a separate cell type, also called synantocytes; Butt et al., 2005); and capillary endothelial cells). Each cell type displays a variety of subcellular structures, in most cells including processes that are

Focal ischemia

Interruption of the supply of oxygen and glucose following blockade of an artery leads to focal ischemia. Unless rapid recanalization occurs, an infarction comprising all cell types begins to develop in the center of the lesion and is fully developed within 1–3 days (Du et al., 1996). Surrounding the infarcted core is a penumbra, which suffers less severe reduction of blood flow because of collateral circulation, and cells here may survive, contingent upon recirculation within a few hours.

Mature brain

Most patients suffering a middle cerebral artery occlusion also have white matter damage (Ho et al., 2005). Consistent with a lower metabolic rate in white matter than in gray matter, both the normal rate of cerebral blood flow and the infarction threshold for cerebral blood flow are lower than in gray matter (Marcoux et al., 1982, Bristow et al., 2005, Demchuk and Mitchell, 2005, Arakawa et al., 2006). However, during permanent artery occlusion in the rat, morphologic changes in subcortical

Concluding remarks

In spite of the different mechanisms by which brain cells die, most or all all succumb to bioenergetic failure, brought about by an increased intracellular Na+ concentration, shown to cause metabolic exhaustion in several cell types, and exacerbating the effects of energy-deprivation per se (Table 5). In most cases the increased Na+ concentration is combined with dysregulation of cytosolic Ca2+ concentration, following NMDA receptor-gated Ca2+ entry and/or reverse operation of the Na+/Ca2+

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