Oxygen Deficiency and Brain Damage: Localization, Evolution in Time, and Mechanisms of Damage

Siesjö, Bo K.

doi:10.3109/15563658508990634

Cited by 23 publications

(8 citation statements)

References 20 publications

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“…Low tissue pH may also cause a nonselective denaturation of proteins and nucleic acids (Kalimo et al, 198 1). Acidosis may also trigger cell swelling via stimulation of the Na+/H+ and Cl-/HCO,-exchangers (Siesjo, 1985;Kimelberg et al, 1990), potentially leading to cellular edema and osmolysis. In addition, acidosis may hinder postischemic metabolic recovery by inhibiting mitochondria1 energy metabolism (Shields et al, 1980;Hillered et al, 1985) and by impairing blood flow via vascular edema.…”

Section: The Traditional Belief In the Acidotic Route Of Ischemic Damagementioning

confidence: 99%

Evolving Concepts About the Role of Acidosis in Ischemic Neuropathology

Tombaugh

Sapolsky

1993

Journal of Neurochemistry

188

109

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Cerebral ischemia is one of the most common neurological insults. Many pathological events are undoubtedly triggered by ischemia, but only recently has it become accepted that ischemic cell injury arises from a complex interaction between multiple biochemical cascades. Tissue acidosis is a well established feature of ischemic brain tissue, but its role in ischemic neuropathology is still not fully understood. Within the last few years, new evidence has challenged the historically negative view of acidosis and suggests that it may play more of a beneficial role than previously thought. This review reintroduces the concept of acidosis to ischemic brain injury and presents some new perspectives on its neuroprotective potential. Key Words: Ischemia-infarction-Lactic acidosis-Excitotoxicity-Hippocampus-Selective neuronal necrosis -Energy metabolism. Experimental work aimed at understanding ischemic brain injury has highlighted numerous biochemical events that may mediate cell damage. Among these, tissue acidosis has received considerable attention. The history of the acidotic concept in ischemia research forms somewhat of an arch. A number of decades ago, cerebral acidosis was shown first to be a correlate of gross ischemic brain damage and was viewed later as a cause. At the height of interest in this topic, acidosis was considered among the principal mechanisms by which ischemic damage occurs (Myers, 1979;Siesjo, 1988~). Even so, it was clear that "cerebral ischemia" was not a single disease but any insult that involved a partial or complete reduction in cerebral blood flow. Various animal models of both focal and global ischemia have been widely used to study ischemic injury, but the question of whether tissue acidosis satisfactorily explains or even contributes to all forms of ischemic brain injury has never been formally addressed.Though acidosis is generally believed to underlie cerebral infarction, mounting evidence has suggested that acidosis does not contribute to the selective neuronal necrosis that occurs after transient ischemia or in the penumbra of developing infarcts. Not surprisingly, the earlier bias toward acidosis as a neurotoxic mechanism has waned. In this review, we briefly examine the evolution of the acidosis concept. We then focus on a recent and surprising series of in vitro observations suggesting that moderate acidosis may actually play a neuroprotective role during ischemia. We then discuss a striking and paradoxical implication of these data regarding the time course and possible mediators of selective neuronal injury following ischemia. THE TRADITIONAL BELIEF IN THE ACIDOTIC ROUTE OF ISCHEMIC DAMAGESupported by varying degrees of experimental evidence, many distinct mechanisms have been proposed to explain ischemic brain injury; of these, the concept of acidotic damage is perhaps the oldest. Early work suggested that metabolic acidosis, caused by continued glycolysis, was responsible for the severe tissue disruption seen in the postmortem brain (Friede and van Houten, 1961). D...

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Section: The Traditional Belief In the Acidotic Route Of Ischemic Damagementioning

confidence: 99%

Evolving Concepts About the Role of Acidosis in Ischemic Neuropathology

Tombaugh

Sapolsky

1993

Journal of Neurochemistry

188

109

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“…Such cell loss, or pannecrosis, in volves both neuronal and nonneuronal cells. Sev eral plausible mechanisms of acidotic neuronal in jury have been proposed (Pulsinelli et aI., 1985;Siesjo, 1985), yet no evidence has linked the ele vated lactate or acidosis directly with the selective loss of certain vulnerable neurons that occurs in the absence of infarct. While these two models need not be mutually exclusive, few attempts have been made to integrate them.…”

mentioning

confidence: 99%

Mechanistic Distinctions between Excitotoxic and Acidotic Hippocampal Damage in an in vitro Model of Ischemia

Tombaugh

Sapolsky

1990

J Cereb Blood Flow Metab

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Summary: Excitotoxicity is believed to underlie the se lective loss of vulnerable neurons after transient isch emia, while lactic acidosis seems to be the principal fea ture and probable cause of tissue infarcts. Primary hip pocampal cultures containing both neurons an d astrocytes derived from fetal rats were used to examine the relative contributions of and interactions between ex citotoxic and acidotic cell injury. Hypoxia-induced dam age was energy dependent and involved the N methyl-D-aspartate (NMDA) receptor. Glucose above 1 mM could completely protect against hypoxia-induced in jury in a pH range of 7.4-6.5, while the NMDA receptor antagonist D,L-2-amino-5-phosphonovaleric acid (500 fLM) during the posthypoxic period provided only partial protection in the absence of glucose. Astrocyte cultures were undamaged by ischemic-like treatment in this pH Transient cerebral ischemia leads to selective and often severe neuron loss. Of those brain regions affected, the CAl cell field in the hippocampus is one of the most vulnerable (Pulsinelli, 1985). Such hippocampal damage, both experimental and spon taneous, can lead to cognitive impairments in pri mates, including humans (Squire, 1987). In animal models, this selective neuronal necrosis seems to arise fr om a process of delayed toxicity fo llowing reperfusion, providing the potential for clinical in tervention. The development of therapeutic strate gies, however, hinges upon a knowledge of the bio chemistry that underlies selective neuronal injury.Received July 12, 1989; revised November 20, 1989; accepted November 21, 1989.Address correspondence and reprint requests to G. C. Tom baugh at Department of Biological Sciences, Stanford Univer sity, Stanford, CA 94305, U.S.A.Abbreviations used: APV, 2-amino-5-phosphonovaleric acid; BSA, bovine serum albumin; DMEM, Dulbecco's Modified Ea gle Medium; KRP, Krebs-Ringer phosphate; LDH, lactate de hydrogenase; NMDA, N-methyl-D-aspartate. 527range, suggesting that hypoxia-induced cell death in mixed cultures was restricted to neurons. Lowering the extracellular pH to 7.0 and 6.5 caused no neuronal dam age in normoxic controls, but in each case provided sig nificant protection against hypoxic neuronal injury. In contrast, a second type of neurotoxicity was observed after a 6-h exposure to pH 6.0, while exposure to pH 5.5 was required to kill astrocytes. This acidotic damage ap peared to be energy independent and did not involve the NMDA receptor. These results suggest that excitotoxic neuron death has an energetic component and that acido sis may produce both protective and damaging effects in the hippocampus during ischemic insults.

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“…This tenet assumes that neuron injury and necrosis are due directly to hypoxia and its consequences (Siesjo, 1985). Strategies which alter neuron responses to hypoxia, including antagonists to neuron NMDA or AMPA ion channel receptors, decrease infarction volume in experimental models of middle cerebral artery occlusion (MCAO) without altering the ischemic stimulus (Dirnagl et al, 1990;Minger et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Focal Cerebral Ischemia Preferentially Affects Neurons Distant from Their Neighboring Microvessels

Mabuchi

Lucero

Feng

et al. 2005

J Cereb Blood Flow Metab

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Developing cerebral infarction obscures the relationship of neurons to their local supply microvessels. We tested the notion that in the basal ganglia (i) an ordered relationship between neurons and their nearest neighboring microvessel exists, and (ii) focal ischemia predictably affects neuron integrity based on microvessel-neuron proximity. Distances between individual microvessels and their nearest neurons ([m-n distance]s) were measured in normal primates and ischemic subjects undergoing middle cerebral artery occlusion for 2 hours. An ordered microvessel-neuron relationship exists in the normal nonischemic basal ganglia within the early hours of focal ischemia. During ischemia normal (n) and sensitive (n*) neurons are interspersed. On average, neurons more distant from their nearest microvessel are most sensitive ([m-n distance] ¼ 16.2711.2 lm versus [m-n* distance] ¼ 22.2713.0 lm, 2P50.00000001). Neurons not expressing glutamic acid decarboxylase were more likely to be sensitive than those with a normal microvessel-neuron relationship. In contrast, the [m-n distance] distribution of injured tyrosine hydroxylase-containing neurons was similar to those without tyrosine hydroxylase. Hence, the [m-n distance] relationship in the normal and ischemic basal ganglia is highly ordered, and distant neurons are consistently perturbed by ischemia, although this is not uniformly dependent on neurotransmitter type.

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Oxygen Deficiency and Brain Damage: Localization, Evolution in Time, and Mechanisms of Damage

Cited by 23 publications

References 20 publications

Evolving Concepts About the Role of Acidosis in Ischemic Neuropathology

Evolving Concepts About the Role of Acidosis in Ischemic Neuropathology

Mechanistic Distinctions between Excitotoxic and Acidotic Hippocampal Damage in an in vitro Model of Ischemia

Focal Cerebral Ischemia Preferentially Affects Neurons Distant from Their Neighboring Microvessels

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