Rats were implanted with 0.3-mm-diameter dialysis tubing through the hippocampus and subsequently perfused with Ringer's solution at a flow rate of 2 microliter/min. Samples of the perfusate representing the extracellular fluid were collected over 5-min periods and subsequently analyzed for contents of the amino acids glutamate, aspartate, glutamine, taurine, alanine, and serine. Samples were collected before, during, and after a 10-min period of transient complete cerebral ischemia. The extracellular contents of glutamate and aspartate were increased, respectively, eight- and threefold during the ischemic period; the taurine concentration also was increased 2.6-fold. During the same period the extracellular content of glutamine was significantly decreased (to 68% of the control value), whereas the concentrations of alanine and serine did not change significantly during the ischemic period. The concentrations of gamma-aminobutyric acid (GABA) were too low to be measured reliably. It is suggested that the large increase in the content of extracellular glutamate and aspartate in the hippocampus induced by the ischemia may be one of the causal factors in the damage to certain neurons observed after ischemia.

Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis

COMPLETE ARREST of the cerebral circulation leads within seconds to cessation of neuronal electrical activity and within a few minutes to deterioration of the energy state and ion homeostasis. Depletion of high energy phosphates, membrane ion pump failure, efflux of cellular potassium, influx of sodium, chloride and water, and membrane depolarization occur swiftly. If such chaos persists for longer than 5-10 minutes, irreversible cell damage is likely. Such is the inevitable sequence of events if blood flow to the brain is arrested. If, however, the ischemia is incomplete the outcome is more difficult to predict and is largely dependent on residual perfusion and oxygen availability. It is in large measure the outcome of incomplete cerebral ischemia, which is of particular interest in cerebrovascular disease. With occlusion of a cere-bral vessel and signs of acute stroke, ischemia is hardly ever total. Some residual perfusion persists in the ischemic area dependent on collateral vessels and local perfusion pressures. Recent evidence indicates that immediate failure of basic functions such as synaptic transmission, ion pumping and energy metabolism in the ischemic brain, is critically dependent on residual blood flow, and that these functions fail at certain critical flow thresholds. It appears, further, that the development of infarction is critically correlated to residual per-fusion, and there is a lethal threshold of residual blood flow below which tissue infarction develops after a certain time. Such knowledge provides the theoretical background for application of the instrumentation now being developed for repeated non-invasive 3-dimensional imaging of residual flow in the ischemic brain. By these means one hopes it will become possible to conduct treatment and to evaluate prognosis in the acute stroke patient by reproducible repeatable measurement in man. In man, flattening of the EEG occurs immediately if hemispheric flow falls below 0.16-0.17 ml-g^min 1 as evidenced by measurements of cerebral blood flow and EEG during clamping of one carotid artery in end-arterectomy. 1-* The critical relationship between cere-bral electrical activity and blood flow which such clinical observation suggested has been amply proven in exDerimental studies. Svmon and Branston and co-workers' demonstrated that the evoked somato-sensory potential recorded in baboon cortex was abolished at local flows below about 0.15 ml'gr^mirr 1. This flow level could be regarded as critical in the sense that electrical function in the cortex was abolished below but sustained above this level. It has, therefore, been referred to as the flow threshold of electrical …

Thresholds in cerebral ischemia - the ischemic penumbra.

All cells in living organisms have a limited life span, and when the time set by their biological clocks has run out, they will die , their highly orga­ nized macromolec ular structure will disintegrate, and the low-molec ul ar degrad ation products be­ come part of the disorder of the surroundings . In thermodynamic terms, this series of events consti­ tutes what has been c alled the entropic doom. We know little about those molec ul ar mechanisms that limit the life span of cells in the absence of dise ase. For the clinician, therefore, the important task is to prevent or tre at dise ases that jeopardize the proper functioning and viability of cells whose biologic al clocks have not yet run out . Measures instituted to prevent brain cell death have a special importance . This i s partly due t o the fact that w e equate human life with the functioning of the brain. However, this importance also resides in the v ulnerability of brain cells to conditions that allow cells of most other tissue to survive , and to continue or res ume their activitie s . The clinically most important conditions leading to brain cell death are those associated with cere­ brovascul ar dise ase, particularly stroke, and with head trauma. We will begin, though, by rec alling the traditional view of the occ urrence and loc alization of neuronal damage in four conditions that lead to more disseminated alterations, e specially since they have been considered to c ause nerve cell injury of a

https://journals.sagepub.com/doi/pdf/10.1038/jcbfm.1981.18

Cell Damage in the Brain: A Speculative Synthesis

The classic concept of the viability thresholds of ischemia differentiates between two critical flow rates, the threshold of electrical failure and the threshold of membrane failure. These thresholds mark the upper and lower flow limits of the ischemic penumbra which is thought ot suffer only functional but not structural injury. Recent studies of the functional and metabolic disturbances suggest a more complex pattern of thresholds. At declining flow rates, protein synthesis is inhibited at first (at a threshold of about 0.55 ml/gm/min), followed by a stimulation of anaerobic glycolysis (at 0.35 ml/gm/min), the release of neurotransmitters and the beginning disturbance of energy metabolism (at about 0.20 ml/min), and finally the anoxic depolariztion (<0.15 ml/gm/min). The penumbra, as defined by the classic flow thresholds, does not remain viable for extended periods. Since viability of the tissue requires maintenance of energy-dependent metabolic processes, penumbra is redefined as a region of constrained blood supply in which the energy metabolism is preserved. Imaging of the penumbra by combining autoradiographic cerebral blood flow measurements with bioluminescent images of adenosine triphosphate (ATP) demonstrates a gradual expansion of the infarct core (in which ATP is depleted) into the penumbra until, after a few hours, the penumbra has disappeared. It is suggested that the limited survival of the penumbra is due to periinfarct depolarizations, which result in repeated episodes of tissue hypoxia, because the increased metabolic workload is not coupled to an adequate increase of collateral blood supply. This explains pharmacological suppression of periinfarct depolarizations lowering the threshold of metabolic disturbances and reducing the volume of the ischemic infarct.

Viability thresholds and the penumbra of focal ischemia.

Effect of anoxia on ion distribution in the brain.

As shown previously, the electrical function of the brain is critically dependent on cerebral blood flow in the sense that reduction beyond an ischemic threshold of approximately 15 ml/100 gm per minute (approximately 35% of control) in the baboon leads to complete failure of the somatosensory evoked response. This study tests the hypothesis that electrical failure in ischemia may be directly associated with a massive release of intracellular K+ or with a critical degree of extracellular acidosis. By microelectrode techniques, measurements of blood flow, extracellular activity of K+ and H+ as well as evoked potential were made in the baboon neocortex. Reductions in blood flow were obtained by occlusion of the middle cerebral artery and depression beyond the ischemic threshold of electrical function achieved by a reduction of systemic blood pressure which, in the ischemic zones, changed local cerebral blood flow proportionally. Abolition of evoked response could not be explained by depolarization by release of intracellular K+, nor was it critically dependent on cortical pH. However, the massive release of intracellular K+ was by itself critically dependent on cortical blood flow and occurred at 18 greater than 6 greater than 2 ml/100 gm per minute (median with 5% confidence limits). Thus a dual threshold in ischemia for neuronal function is described, the threshold for release of K+ being clearly lower than the threshold for complete electrical failure. Further, the findings support the concept of an ischemic penumbra during which the neurons remain structurally intact but functionally inactive. That neurons can survive for some time in this state of lethargy is evidenced by the observations that an increase in rCBF, if sufficient, can restore evoked potential and normalize extracellular K+ activity as well as pH.

Cortical evoked potential and extracellular K+ and H+ at critical levels of brain ischemia.

Function and metabolism of the brain are critically dependent on a sufficient oxygen supply. In man, cerebral blood flow (CBF) is about 50 ml/100 gm/min and the arteriovenous differences for oxygen (AVDO2) about 7 vol%, giving a cerebral oxygen consumption (CMRO2) of about 3.5 ml/100 gm/min. If CBF is moderately reduced as in the state of oligemia, the flow reduction will be balanced by a rise in AVDO2 so that a normal oxygen supply is maintained. A further reduction in CBF may still be balanced while AVDO2 approximates the arterial oxygen content, and at a normal metabolic rate, flow reductions down to about 20 ml/100 gm/min may be tolerated. This flow level is critical in the sense that below this level oxygen is insufficiently supplied, and since the AVDO2 is maximal, the CMR02 is given by the blood flow (ischemia) (Fig. l).Thus in the ischemic flow ranges a further reduction in flow enforces a proportional reduction in oxygen consumption. Experimentally this principle allows a determination of the critical low levels of local oxygen supply, given as local blood flow (CBF), leading to failure of fundamental brain tissue functions.

Thresholds of cerebral ischemia

The effects of ischaemia on the central nervous system have been the subject of much experimental and clinical investigation. Occlusion of the middle cerebral artery in baboons simulates the production of an acute clinical stroke (Harvey and Rasmussen,1951, Symon, 1961, Symon et al, 1974, Symon et al, 1972, Yagamuchi et al, 1971) and produces an ischaemic lesion whose extent is restricted to known regions of the cerebral hemisphere and which therefore interferes only selectively with the neural pathways. We have shown (Symon et al, 1974) that the density of ischaemia produced by occlusion of the middle cerebral artery is graded over the surface of the hemisphere, and, for example, that areas of the sensori-motor strip, show varying levels of residual blood flow. Since the thalamic nuclei are not significantly affected by occlusion of the middle cerebral artery (Kaplan and Ford, 1966, Lazorthes and Campan, 1964) the electrical activity of the sensorimotor strip assessed as the somatosensory evoked response may be measured in relation to regional changes in tissue blood flow.

N. A. Lassen

Papers

Cortical evoked potential and extracellular K+ and H+ at critical levels of brain ischemia.

Thresholds of cerebral ischemia

Thresholds of ischaemia in brain cortex.