Hypoxic-ischemic cerebral necrosis in midgestational sheep fetuses: Physiopathologic correlations

Ting, Pauline C.; Yamaguchi, S; Bacher, John; Killens, Richard; Myers, Ronald E.

doi:10.1016/0014-4886(83)90019-5

Cited by 66 publications

(22 citation statements)

References 23 publications

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“…Although the threshold concentration of lactic acid required to damage the brain in the fetus is un known, the correlation of our present results with our earlier sheep fetal neuropathologic findings (Ting et al , 1983) suggests this threshold concen tration is likely to be in the same range as for the adult. That is, normotensive hypoxic fetuses accu mulated lactic acid in many brain structures to 7 -13 f,Lmol/g and remained brain intact.…”

Section: Discussionsupporting

confidence: 77%

“…In our previous study (Ting et al , 1983), the ewes of fetuses that became hypotensive and developed damage in their brains received significantly lower quantities of pentobar bital during exposure. Since sheep rapidly metabo lize pentobarbital, additional doses were regularly administered (about every 20 min) to the ewes.…”

Section: Discussionmentioning

confidence: 86%

“…Identical le sions develop in human fetuses exposed to severe intrauterine asphyxia (Hallervorden, 1944;Friede, 1975) or that suffer cerebral circulatory distur bances (Friede, 1975). Studies in our laboratory by Ting et al (1983) demonstrated that mid-gestational sheep fetuses subjected to 2 h of marked hypoxia develop damage to their brains only in those instances when MABP is reduced to values of <30 mm Hg. Such fetuses developed extensive zones of focal necrosis af fecting widespread brain areas including the neo striatum, cerebral white matter, and, less mark edly, the overlying cortex.…”

mentioning

confidence: 91%

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Brain Metabolic Correlates of Hypoxic-Ischemic Cerebral Necrosis in Mid-Gestational Sheep Fetuses: Significance of Hypotension

Wagner

Ting

Westfall

et al. 1986

J Cereb Blood Flow Metab

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Summary: Midgestational sheep fetuses exposed to marked hypoxia for 2 h remain brain intact if MABP is maintained above 30 mm Hg. On the other hand, simi larly hypoxic fetuses, if they experience reductions in MABP below 30 mm Hg, develop foci of necrosis that predominantly affect hemispheric white matter and neo striatum. Cortex damage is more restricted and is usually associated with more massive underlying white matter damage. The present study examines the brain metabolic basis for the important role of hypotension in brain injury development in marked hypoxia. Sheep fetuses rendered hypoxic by respiring their ewes with 11 % oxygen (fetal PaOZ = 8-12 mm Hg) in which MABP was maintained above 30 mm Hg showed increases in brain lactic acid concentrations to 7 -13 f,Lmollg but unaltered energy charge. In contrast, fetuses that sustained MABP reduc tions below 30 mm Hg showed increases in lactic acid Fetal or neonatal hypoxic-ischemic encephalo pathy is commonly thought to result from an im paired oxygen supply to brain due to a decreased oxygen content of arterial blood and/or a decrease in CBF. Such asphyxia in utero, in contrast to various postnatal insults, is the predominant cause of "cerebral palsy," a syndrome that encompasses a variety of motor deficits and in which mental re tardation and epilepsy may or may not be present (Volpe, 1981).The neuropathology of perinatal hypoxic-isch emic encephalopathy includes selective neuronal Received July 8, 1985; accepted March 25, 1986. Address correspondence and reprint requests to Dr. K. R. Wagner at Veterans Administration Medical Center, Medical Research Service/15I , 3200 Vine Street, Cincinnati, OH 45220, U. S. A. 425concentrations in vulnerable structures to 16-24 f,Lmol/g accompanied by marked decreases in energy charge. The vulnerable structures also showed reductions in fructose concentrations but a variable behavior of other brain me tabolites including phosphocreatine, glycogen, and glu cose. Thus, the present findings suggest a relation be tween hypotension during marked hypoxia, low energy charge, lactic acid accumulation in brain at high concen trations, and fetal brain injury. The ewes of hypoxic hy potensive fetuses received pentobarbital at lower doses than did those of fetuses that maintained blood pressure. This suggests that pentobarbital plays an important role in protecting the fetal brain from asphyxia by extending the hypoxic fetus's ability to maintain blood pressure in addition to reducing its brain metabolism.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 86%

mentioning

confidence: 91%

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Brain Metabolic Correlates of Hypoxic-Ischemic Cerebral Necrosis in Mid-Gestational Sheep Fetuses: Significance of Hypotension

Wagner

Ting

Westfall

et al. 1986

J Cereb Blood Flow Metab

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“…Because studies of ischemic animal models (derived principally from mature animals) suggest that high lactate concentrations may mediate hypoxic cell death and that there is a critical threshold of approximately 16-20 mM lactate above which cell death occurs (8,(18)(19)(20), we evaluated the relation of medium lactate concentrations to LDH efflux of cells made hypoxic. Thus, cells were exposed to 24 h of hypoxia in various concentrations of glucose (Fig.…”

Section: Relation Of Lactate Concentration To Ldh E$jux Of Hypoxic Cementioning

confidence: 99%

“…Second, because in a variety of in vivo models of hypoxicischemic injury there is controversy regarding whether glucose supplementation is beneficial or deleterious (8)(9)(10)(11)(12)(13)(14)(15)(16)(17), we studied the effect of exogenous glucose levels on vulnerability to hypoxia. Third, because in a variety of in vivo models of hypoxic-ischemic injury there is controversy regarding the role of high lactate levels in the mediation of cell death (8,10,13,15,(18)(19)(20)(21), we determined the relation of extracellular lactate levels to the degree of hypoxic astrocytic injury.…”

mentioning

confidence: 99%

Hypoxic Injury to Developing Glial Cells: Protective Effect of High Glucose

1990

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ABSTRACT. Hypoxic injury to differentiating glial cells is a critical event in the development of periventricular leukomalacia, the major hypoxic-ischemic lesion of the premature infant. This study has addressed the effects of hypoxia on differentiating glial cells, primarily astrocytes. Primary cultures of dissociated newborn rat brain, which are composed predominantly of differentiating astroglia, were used. Efflux of lactate dehydrogenase, an enzyme enriched in astroglia, was used to quantitate cellular injury. Three major findings are reported. First, differentiating astrocytes were resistant to hypoxic injury for many hours, although by 24 h of hypoxia severe cellular injury (lactate dehydrogenase efflux of 86% of total and morphologic changes) was obvious. Second, increase of glucose in the culture medium from the approximately physiological concentration of 5.6 to 15 mM had a marked protective effect versus hypoxia, i.e. lactate dehydrogenase efflux was totally prevented during 24 h of hypoxia in 15 mM glucose.-Third, the protective effect of high glucose appeared to be related to increased utilization by glycolysis, because there was a direct correlation between the resistance to hypoxic cellular injury and the amount of lactate generated and of glucose consumed by the cells. Thus, the cells with the lowest lactate dehydrogenase efflux (and highest glucose supplementations) had medium lactate concentrations as high as 32-36 mM. These concentrations of lactate are approximately double the reported threshold concentration of lactate considered to produce cellular necrosis in in vivo models of hypoxic injury, primarily in mature animals. The data raise the possibility that hypoxic injury to differentiating glia can be prevented or ameliorated by increase in glucose availability. (Pediatr Res 27: 186-190, 1990) Abbreviations DMEM, Dulbecco's modified Eagle's medium LDH, lactate dehydrogenase elucidation of the mechanisms of neuronal death with hypoxia. Indeed studies of neurons in cell cultures (2,3), as well as in other experimental models (4), have emphasized the importance of excitatory amino acid neurotransmitters in the mediation of hypoxic neuronal death. However, relatively little work has been directed toward elucidation of mechanisms of hypoxic death of glia, especially developing glia. The particular importance of this research for the neonatal period is related to the fact that the dominant neuropathology in the human premature infant subjected to hypoxic-ischemic insult is not neuronal injury but rather injury to periventricular white matter, rich in developing glia but devoid of neurons (1). Neuropathologic data indicate that the glial cell is the particular target of such hypoxic injury (5,6). The particular glial cell type(s) most affected are not yet known conclusively.In this study we use a model of developing glial cells, i.e. primary glial cell cultures derived from newborn rat brain. Although containing both developing astrocytes and oligodendroglia, these cultures are composed of appr...

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Regulation of the Cerebral Circulation During Development

Koehler

2021

Comprehensive Physiology

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Hypoxic-ischemic cerebral necrosis in midgestational sheep fetuses: Physiopathologic correlations

Cited by 66 publications

References 23 publications

Brain Metabolic Correlates of Hypoxic-Ischemic Cerebral Necrosis in Mid-Gestational Sheep Fetuses: Significance of Hypotension

Brain Metabolic Correlates of Hypoxic-Ischemic Cerebral Necrosis in Mid-Gestational Sheep Fetuses: Significance of Hypotension

Hypoxic Injury to Developing Glial Cells: Protective Effect of High Glucose

Regulation of the Cerebral Circulation During Development

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