Heterogeneous Distribution of Hydrogen and Bicarbonate Ions During Complete Brain Cischemia

Kraig, Richard P.; Pulsinelli, William A.; Plum, Fred

doi:10.1016/s0079-6123(08)61981-0

Cited by 47 publications

(31 citation statements)

References 49 publications

(64 reference statements)

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“…In addition, animals were normoxic, normoglycemic, and had normal hematocrits and body temperatures. Brain physiologic variables (Table 2) (Kraig et al 1983(Kraig et al ,1985a(Kraig et al ,1985b(Kraig et al ,1986 (Siesjö 1985), should encourage others to apply similar measurements to areas of interest. Perhaps the most important aspect of the present combined electrode experiments is the speed in which changes in carbonic acid buffer species and ammonia buffer species can be measured.…”

Section: Resultsmentioning

confidence: 99%

“…Spreading depression is associated with an alkaline, then acid-going shift in interstitial [H + (Kraig et al 1983;Mutch and Hansen 1984;Kraig et al 1985a). In rat neocortex, lactate accumulates to 7 mmol/kg (Mutch and Hansen 1984) and associated hydrolysis of high-energy phosphate stores (Alberti and Cuthbert 1982) probably accounts for the increased proton production of brain undergoing spreading depression.…”

Section: Introductionmentioning

confidence: 99%

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Bicarbonate and ammonia changes in brain during spreading depression

Kraig¹,

Cooper²

1987

Can. J. Physiol. Pharmacol.

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An alkaline, followed by an acid-going transient, characterizes acid-base changes in the interstitial space during spreading depression in a variety of brain structures. In rat, such changes are associated with a significant rise in brain lactate content. How brain proton buffers behave during spreading depression is unknown. Techniques to significantly improve the response time of gas permeable membrane semnimicroelectrodes for carbon dioxide and ammonia are reported. Measurements with such electrodes, when coupled to measurements of hydrogen ion concentration (from microelectrodes), permit rapid changes to be determined in bicarbonate concentration or ammonia and ammonium ion concentration, respectively. Bicarbonate concentration fell from 30 ± 1 (n = 16) to 14 ± 1 mM (n = 16) during spreading depression. On the other hand, ammonia concentration rose from 2.3 ± 0.1 to 4.4 ± 0.3 μM (n = 17) while ammonium ion concentration rose from 116 ± 11 (n = 17) to 382 ± 30 μM (n = 17) during spreading depression. Bicarbonate changes probably reflect titration of brain bicarbonate stores by accumulated lactic acid. Similar physicochemical changes do not explain the rise in ammonia and ammonium ion concentrations. Instead, elevation of the latter can only result from an increase in ammonia content of the interstitial space.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Bicarbonate and ammonia changes in brain during spreading depression

Kraig¹,

Cooper²

1987

Can. J. Physiol. Pharmacol.

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“…Not surprisingly, oxygen deprivation in rodents enhances cerebral glucose uptake and utilization (Torbati et al, 1986;Izumiyama et al, 1987) and evokes a pronounced rise in tissue lactate (Pulsinelli and Duffy, 1983). As ATP consumption outstrips production, and as [H+Ii exceeds the buffering capacity within ischemic brain cells, protons are exported via active extrusion mechanisms to the interstitial space where they accumulate (Hansen, 1978;Kraig et al, 1985). However, the rapid loss of Na+,K+-ATPase pump activity during periods of energy depletion compromises the Na+ gradient, impairing both H+ and HCO,-exchange systems.…”

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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“…1,2 Spreading depolarization imposes a large metabolic burden on brain tissue, evidenced by depletion of energy substrates and O 2 3,4 and by accumulation of metabolic byproducts such as lactate and H + . 5,6 ATP concentration drops by nearly 50% during SD in normoxic conditions, 7 and metabolic depletion is expected to be more severe when occurring in tissue with limited substrate availability.Recent clinical studies strongly suggest that SD is involved in the pathophysiology of migraine with aura, thromboembolic stroke, traumatic brain injury, and subarachnoid hemorrhage. 8 While normoxic, normoglycemic SD can be noninjurious, 9 SD in the setting of metabolic compromise exacerbates neuronal injury.…”

mentioning

confidence: 99%

Spreading Depolarization-Induced Adenosine Accumulation Reflects Metabolic Status In Vitro and In Vivo

Lindquist

Shuttleworth

2014

J Cereb Blood Flow Metab

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Spreading depolarization (SD), a pathologic feature of migraine, stroke and traumatic brain injury, is a propagating depolarization of neurons and glia causing profound metabolic demand. Adenosine, the low-energy metabolite of ATP, has been shown to be elevated after SD in brain slices and under conditions likely to trigger SD in vivo. The relationship between metabolic status and adenosine accumulation after SD was tested here, in brain slices and in vivo. In brain slices, metabolic impairment (assessed by nicotinamide adenine dinucleotide (phosphate) autofluorescence and O 2 availability) was associated with prolonged extracellular direct current (DC) shifts indicating delayed repolarization, and increased adenosine accumulation. In vivo, adenosine accumulation was observed after SD even in otherwise healthy mice. As in brain slices, in vivo adenosine accumulation correlated with DC shift duration and increased when DC shifts were prolonged by metabolic impairment (i.e., hypoglycemia or middle cerebral artery occlusion). A striking pattern of adenosine dynamics was observed during focal ischemic stroke, with nearly all the observed adenosine signals in the periinfarct region occurring in association with SDs. These findings suggest that adenosine accumulation could serve as a biomarker of SD incidence and severity, in a range of clinical conditions. Keywords: acute stroke; adenosine; brain slice; electrophysiology; energy metabolism; spreading depression INTRODUCTION Spreading depolarization (SD) of brain tissue is a self-propagating wave of neuronal and glial activation, carried by large transmembrane currents that depolarize cells and disrupt ionic gradients. 1,2 Spreading depolarization imposes a large metabolic burden on brain tissue, evidenced by depletion of energy substrates and O 2 3,4 and by accumulation of metabolic byproducts such as lactate and H + . 5,6 ATP concentration drops by nearly 50% during SD in normoxic conditions, 7 and metabolic depletion is expected to be more severe when occurring in tissue with limited substrate availability.Recent clinical studies strongly suggest that SD is involved in the pathophysiology of migraine with aura, thromboembolic stroke, traumatic brain injury, and subarachnoid hemorrhage. 8 While normoxic, normoglycemic SD can be noninjurious, 9 SD in the setting of metabolic compromise exacerbates neuronal injury. 10,11 Work in animal models has identified delayed repolarization, marked by prolonged extracellular direct current (DC) shifts, as a hallmark of injurious SD in metabolically compromised tissue. 10 Observational studies in human subjects have confirmed the association between prolonged DC shifts and poor outcome after SD, 12 but human studies have so far been limited by the requirement for invasive electrical recordings in patients with craniotomies. It would be helpful to establish additional biomarkers of metabolic status, to assess vulnerability to SD in injured brain.Extracellular adenosine accumulation can serve as a global indicator of energy charge....

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Heterogeneous Distribution of Hydrogen and Bicarbonate Ions During Complete Brain Cischemia

Cited by 47 publications

References 49 publications

Bicarbonate and ammonia changes in brain during spreading depression

Bicarbonate and ammonia changes in brain during spreading depression

Evolving Concepts About the Role of Acidosis in Ischemic Neuropathology

Spreading Depolarization-Induced Adenosine Accumulation Reflects Metabolic Status In Vitro and In Vivo

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