Fructose-1,6-Bisphosphate Protects Astrocytes from Hypoxic Damage

Gregory, George; Yu, Annie; Chan, Pak H.

doi:10.1038/jcbfm.1989.4

Cited by 57 publications

(24 citation statements)

References 18 publications

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“…No protective effect was observed with any of the additions (data not shown). The lack of protective effect of fructose-l,6-diphosphate is unlike observations made with fully differentiated astrocytes (39).…”

Section: Effect Of Glucose On Hypoxia-induced Ldh Djuxcontrasting

confidence: 56%

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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Section: Effect Of Glucose On Hypoxia-induced Ldh Djuxcontrasting

confidence: 56%

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

1990

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“…1), reducing mortality during the ischemic period and the earlier phase of recirculation, but exerting only a modest protection against the overall mortality after 8 days of recirculation (i.e., when the histological damage was quantified). All these results appear to agree with some previous observa tions (11,12,15,16). When comparing, however, the results of the present study with others, a couple of fac tors should be considered.…”

Section: Resultssupporting

confidence: 92%

“…Conversely, studies based on [14C]FBP uptake in erythrocytes demonstrated that the compound does not enter the cell (17,18). Fur thermore, no evidence has been provided until now that FBP is taken up by brain cells, although recently, in an experiment conducted on isolated cortical astrocytes in vitro, a rapid incorporation of FBP into cells has been reported (11). Moreover, this phenomenon seems to be energy-dependent since it decreased by nearly 70076 when the temperature was reduced from 37 to 01C.…”

Section: Resultsmentioning

confidence: 99%

“…In their model, Farias and col leagues administered the compound during the blood flow interruption and continued the infusion after recircu lation. Gregory and colleagues (11), on the other hand, observed that FBP exerted its protective effect in cultured rat astrocytes subjected to hypoxia only when it was as sociated with glucose. It should also be noted that FBP was already present in the medium when hypoxia was ini tiated.…”

Section: Resultsmentioning

confidence: 99%

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Improvement of Ischemic Myocardial Dysfunction by Nisoldipine in Relation to Its Coronary Vasodilating Action

Trimarchi

Arcadi

Luca

et al. 1993

Japanese Journal of Pharmacology

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ABSTRACT-We examined the protective activity of fructose l,6-bisphosphate (FBP) on mortality and delayed hippocampal cell death induced by transient cerebral ischemia in the Mongolian gerbil. Forebrain ischemia was produced by bilaterally occluding the common carotid arteries for 15 min using micro aneurysm clips; then the blood supply to the brain was restored. The number of survivors was counted for 8 days, and the histopathological damage in the CAI region of the hippocampus was scored according to the semiquantitative scale of Rudolphi and colleagues. When injected 15 min before the ischemic insult, FBP (100 and 333 mg/kg, i.v.) significantly reduced the rate of mortality during the 8-day observation period. Equivalent doses of fructose and fructose monophosphate did not improve survival, and neither did low doses (33 mg/kg) of FBP. FBP also produced a significant degree of protection against the CAI pyramidal cell loss in comparison with its vehicle (distilled water). Conversely, when we administered the compound, at the same dose, 15 min after the release of the arterial occlusion, we observed neither a significant reduc tion of mortality nor significant protection against hippocampal CAI pyramidal cell loss. These results sug gest that FBP possesses salutary properties against the damages induced by transient cerebral ischemia, although they are evident only when the compound is administered before the resolution of the ischemic injury.

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“…23 -2641 - 43 Recently, Gregory et al 43 reported that FDP protects astrocytes subjected to 18 hours of normothermic anoxia. In addition, these authors measured the uptake of radiolabeled FDP and found it to be rapidly incorporated into the cell fraction of normoxic astrocytes.…”

Section: Figure 3 Electroencephalograms (Eegs) Before (Control) and mentioning

confidence: 99%

Prevention of ischemic-hypoxic brain injury and death in rabbits with fructose-1,6-diphosphate.

Farias

Smith

Markov

1990

Stroke

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Fructose-l,6-diphosphate has been shown to improve neurologic recovery following resuscitation from cardiac arrest and to restore brain electrical activity during hypoglycemic coma in rabbits. In view of these findings, we determined whether fructose-1,6-diphosphate protects the brain during ischemia-hypoxia. We subjected 16 rabbits to hypotension, hypoxemia, and bilateral common carotid artery occlusion. Five minutes after the onset of isoelectric electroencephalograms, seven randomly selected rabbits received 10% fructose-l,6-diphosphate (350 mg/kg bolus followed by 10 mg/kg/min infusion for 90 minutes) and the remaining nine rabbits (controls) received an equal volume of 1.5% NaCl (3.5 ml/kg bolus followed by 0.1 ml/kg/min infusion for 90 minutes). After isoelectricity lasting 7.86±0.8 minutes (mean±SEM) in the treated group and 6.44 ±0.38 minutes in the control group, the rabbits were reinfused with autologous shed blood and reoxygenated and the carotid artery occluders were removed. Treated rabbits recovered electrical activity more rapidly than the controls (p<0.005), and all seven treated rabbits survived. Only two controls (22%) survived (p<0.001), and they were severely disabled. Histology showed extensive cortical necrosis and focal necrosis in the hippocampi and cerebellum of brains from the two surviving controls. Brains from two treated rabbits exhibited minimal neuronal loss limited to the neocortex, and the brains from the remaining five treated rabbits were normal. This study suggests that fructose-1,6 -diphosphate protects the brain from ischemic-hypoxic insults.

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Fructose-1,6-Bisphosphate Protects Astrocytes from Hypoxic Damage

Cited by 57 publications

References 18 publications

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

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

Improvement of Ischemic Myocardial Dysfunction by Nisoldipine in Relation to Its Coronary Vasodilating Action

Prevention of ischemic-hypoxic brain injury and death in rabbits with fructose-1,6-diphosphate.

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