The mechanism of cerebral hypoxic‐ischemic damage

Schurr, Avital; Rigor, Benjamin M.

doi:10.1002/hipo.450020303

Cited by 70 publications

(28 citation statements)

References 96 publications

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“…It has been demonstrated that during ischemic states, brain production of free radicals such as superoxide causes increased re lease of excitatory amino acids which are endowed with neurotoxic effects (Pellegrini-Giampietro et ai., 1990). Also, the free radical hypothesis in hyp oxic-ischemic cell injury shares a common path with the excitotoxic hypothesis, i.e., its depen dence on calcium (Orrenius et ai., 1989), and it has been proposed that free radicals, either alone or in combination with excitatory amino acids, may en hance calcium influx and overload to exacerbate neuronal damage (Halliwell, 1992;Schurr and Rigor, 1992).…”

Section: Discussionmentioning

confidence: 99%

A Simple Method for Evaluation of Superoxide Radical Production in Neural Cells under Various Culture Conditions: Application to Hypoxia

Daval

Ghersi‐Egea

Oillet³

et al. 1995

J Cereb Blood Flow Metab

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Summary: To evaluate the potential deleterious influence of oxygen-derived free radicals following hypoxia in a model of primary culture of neurons obtained from the fetal rat brain, superoxide radicals were measured as a function of time in the extracellular medium. Neuronal cells were grown for 8 days in the presence or absence of serum, then incubated in a buffered Krebs-Ringer solu tion containing 60 j..l. M acetyl-cytochrome c. The rate of superoxide radical formation was quantified spectropho tometrically by measuring the specific reduction of acetyl-cytochrome c. Under normoxic conditions (95% air-5% CO2), basal production of superoxide that in creased with time was recorded. It was significantly more

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Section: Discussionmentioning

confidence: 99%

A Simple Method for Evaluation of Superoxide Radical Production in Neural Cells under Various Culture Conditions: Application to Hypoxia

Daval

Ghersi‐Egea

Oillet³

et al. 1995

J Cereb Blood Flow Metab

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“…As this field has matured, a host of potential mediators of ischemic injury has been described: EAAs, free cytosolic Ca*+, acidosis, oxygen radicals, and so on. As a source of considerable tautological confusion, each of these putative mediators of injury can potentially interact with and exacerbate the toxicity of others (Siesjo, 1988b;Schurr and Rigor, 1992). These interactions emphasize the importance of defining a temporal sequence of the various biochemical derangements induced by ischemia, a task made more difficult by the heterogeneity of experimental systems used to model the disorder.…”

Section: Discussionmentioning

confidence: 99%

“…In the context of selective neuronu1 vulnerability, though, the relationship between acidosis and ischemic cell injury is less obvious. However convincing the acidotic hypothesis may have been, recent work has cast doubt about its primacy, emphasizing that acidosis is only part of a complex and dynamic series of events in the ischemic brain (Schurr and Rigor, 1992). …”

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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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“…Some investigators have reported reduced neuronal injury from oxygen deprivation using glutamate antagonists in dissociated cell cultures (Goldberg et al, 1987;Marcoux et al, 1990) or in acutely prepared hippocampal slices (Clark and Rothman, 1987). Other investigators have reported that glutamate receptor antagonists do not effectively reduce neuronal damage following oxygen deprivation alone (Aitken et al, 1988;Lipton and Lobner, 1990;Schurr and Rigor 1992;Friedman and Haddad, 1993;Haddad and Jiang, 1993). These previous studies raise the possibility that the nature and severity of the insult.…”

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confidence: 80%

Glutamate and non-glutamate receptor mediated toxicity caused by oxygen and glucose deprivation in organotypic hippocampal cultures

et al. 1995

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In vitro ischemia models have utilized oxygen, or oxygen and glucose deprivation to simulate ischemic neuronal injury. Combined oxygen and glucose deprivation can induce neuronal damage which is in part mediated through NMDA receptors. Severe oxygen deprivation alone however can cause neuronal injury which is not NMDA mediated. We tested the hypothesis that NMDA, or non-NMDA receptor mediated mechanisms may predominate, to induce neuronal injury following severe oxygen deprivation depending on the presence of glucose. We found that NMDA receptor blockade using dizocilpine (MK-801), DL-2-amino-5- phosphonovaleric acid (APV), or CGS 19755, was highly effective in reducing CA1 injury in organotypic hippocampal cultures, caused by complete oxygen and glucose deprivation. Complete oxygen deprivation alone however, caused CA1 neuronal injury which was not diminished using NMDA receptor blockade alone with MK-801 or APV, or in combination with AMPA/kainate receptor blockade using 6-cyano-7- dinitroquinoxalone-2,3-dione (CNQX). Neuronal protective strategies which act primarily through non-glutamate dependent mechanisms, including hypothermia, low chloride and calcium, and the free radical scavenger, alpha-phenyl-tert-butyl nitrone (PBN), provided neuronal protection against complete oxygen, as well as combined oxygen/glucose deprivation. Raising the pH using Hepes buffer during complete oxygen deprivation did not result in neuronal protection by NMDA receptor blockade. Partial oxygen deprivation alone, partial oxygen deprivation combined with glucose deprivation, glucose deprivation alone, and also glutamate exposure, all produced neuronal damage that was reduced by NMDA receptor blockade. The presence of glucose during complete oxygen deprivation appears to prevent glutamate receptor blockade from reducing neuronal injury in organotypic hippocampal cultures.

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The mechanism of cerebral hypoxic‐ischemic damage

Cited by 70 publications

References 96 publications

A Simple Method for Evaluation of Superoxide Radical Production in Neural Cells under Various Culture Conditions: Application to Hypoxia

A Simple Method for Evaluation of Superoxide Radical Production in Neural Cells under Various Culture Conditions: Application to Hypoxia

Evolving Concepts About the Role of Acidosis in Ischemic Neuropathology

Glutamate and non-glutamate receptor mediated toxicity caused by oxygen and glucose deprivation in organotypic hippocampal cultures

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