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Energy metabolism in hypoxic astrocytes: Protective mechanism of fructose-1,6-bisphosphate

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Abstract

The protective effects of fructose-1,6-biphosphate (FBP) during hypoxia/ischemia are thought to result from uptake and utilization of FBP as a substrate for glycolysis or from stimulation of glucose metabolism. To test these hypotheses, we measumed CO2 and lactate production from [6-14C]glucose, [1-14C]glucose, and [U-14C]FBP in normoxic and hypoxic cultured astrocytes with and without FBP present. FBP had little effect on CO2 production by glycolysis, but increased CO2 production by the pentose phosphate pathway. Labeled FBP produced very small amounts of CO2. Lactate production from [1-, and 6-14C]glucose increased similarly during hypoxic hypoxia; the increase was independent of added FBP. Labeled lactate from [U-14C]FBP was minimal. We conclude that exogenous FBP is not used by astrocytes as a substrate for glycolysis and that FBP alters glucose metabolism.

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References

  1. Farias, L. A., Smith, E. E., and Markov, A. K. 1990. Prevention of ischemic-hypoxic brain injury and death in rabbits with fructose-1,6-diphosphate. Stroke 21:606–613.

    PubMed  Google Scholar 

  2. Farias, L. A., Sun, J., and Markov, A. K. 1989. Improved brain metabolism with fructose 1–6 diphosphate during insulin-induced hypoglycemic coma. Am. J. Med. Sci 297:294–299.

    PubMed  Google Scholar 

  3. Farias, L. A., Willis, M., and Gregory, G. A. 1986. Effects of fructose-1,6-diphosphate, glucose, and saline on cardiac resuscitation. Anesthesiology 65:595–601.

    PubMed  Google Scholar 

  4. Kuluz, J. W., Gregory, G. A., Han, Y., Deitrich, D., and Schlein, C. L. 1993. Fructose-1,6-bisphosphate reduces infarct volume after reversible middle cerebral artery occlusion in rats. Stroke 24: 1576–1583.

    PubMed  Google Scholar 

  5. Trimarchi, G. R., De Luca, R., Campo, G. M., Scuri, R., and Caputi, A. P. 1990. Protective effects of fructose-1,6-bisphosphate on survival and brain putrescine levels during ischemia and recirculation in the mongolian gerbil. Stroke (Suppl iv):iv-171–iv-173;.

    Google Scholar 

  6. Gregory, G. A., Yu, A. C. H., and Chan, P. H. 1989. Fructose-1,6-bisphosphate protects astrocytes from hypoxic damage. J. Cereb. Blood Flow & Metab. 9:29–34.

    Google Scholar 

  7. Gregory, G. A., Welsh, F. A., Yu, A. C. H., and Chan, P. H. 1991. Fructose-1,6-bisphosphate reduces ATP loss from hypoxic astrocytes. Brain Res. 516:310–312.

    Google Scholar 

  8. Hassinen, I. E., Nuutinen, E. M., Ito, K., Nioka, S., Lazzarino, G., Giardina, B., and Chance, B. 1991. Mechanism of the effect of exogenous fructose 1,6-bisphosphate on myocardial energy metabolism. Circulation 83:584–593.

    PubMed  Google Scholar 

  9. Heckler, F. R., Markov, A. K., White, T. Z., and Jones, E. W. 1983. Effect of fructose-1,6-diphosphate (FDP) on canine hind limbs subjected to tourniquet ischemia. J. Hand Surg. (Am.) 8: 622–623.

    Google Scholar 

  10. Markov, A. K. 1986. Hemodynamics and metabolic effects of fructose 1–6 diphosphate in ischemia and shock—experimental and clinical observations. Annals Emer. Med. 15:1470–1477.

    Google Scholar 

  11. Lowry, O. H., Passonneau, J. V. 1964. The relationship between substrates and enzymes of glycolysis in brain. J. Biol. Chem. 239: 31–42.

    PubMed  Google Scholar 

  12. Norberg, K., and Siesjo, B. K. 1975. Cerebral metabolism in hypoxic hypoxia I. Pattern of activation of glycolysis: A reevaluation. Brain Res. 8:31–44.

    Google Scholar 

  13. Lowry, O. H., and Passonneau, J. V. 1966. Kinetic evidence for multiple binding sites on phosphofructokinase. J. Biol. Chem. 241: 2268–2279.

    PubMed  Google Scholar 

  14. Mansour, T. E. 1963. Studies on heart phosphofructokinase: purification, inhibition, and activation. J. Biol. Chem. 238:2286–2292.

    Google Scholar 

  15. Rigobello, M. P., Bianchi, M., Deana, R., and Galzigna, L. 1982. Interaction of fructose-1,6-diphosphate with some cell membranes. Agressologie 23:63–66.

    Google Scholar 

  16. Galzigna, L., Rizzoli, V., Bianchi, M., Rigobello, M. P., and Scuri, R. 1989. Some effects of fructose-1,6-diphosphate on rat myocardial tissue related to a membrane-stabilizing action. Cell Biochem. Function. 7:91–96.

    Google Scholar 

  17. Booher, H., and Sensenbrenner, M. 1972. Growth and cultivation of dissociated neurons and glial cells from embryonic chick, and rat brain in flask cultures. Neurobiology 2:97–105.

    PubMed  Google Scholar 

  18. Yu, A. C. H., Chan, P. H., and Fishman, R. A. 1986. Effects of arachidonic acid on glutamate and γ-aminobutyric acid uptake in primary cultures of rat cerebral astrocytes and neurons. J. Neurochem. 47:1181–1189.

    PubMed  Google Scholar 

  19. Hertz, L., Juurlink, B. H. J., and Szuchet, S. 1985. Cell cultures. Pages 603–666, in Laitha, A. (ed.), Handbook of Neurochemistry, Vol. 8, 2nd Edition, Plenum Press, New York.

    Google Scholar 

  20. Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J. 1951. Protein measurements with the Folin phenol reagent. J. Biol. Chem. 193:265–275.

    PubMed  Google Scholar 

  21. Itoh, T., and Quastel, J. H. 1975. Acetoacetate metabolism in infant and adult brain in vivo. Biochem. J. 116:641–655.

    Google Scholar 

  22. Edmond, J., Robbins, R. A., Bergstrom, J. D., Cole, R. A., and deVellis, J. 1987. Capacity for substrate utilization in oxidative metabolism by neurons, astrocytes, and oligodendrocytes from developing brain in primary culture. J. Neurosci. Res. 18:551–561.

    PubMed  Google Scholar 

  23. Horowicz, P., and Larrabee, M. G. 1962. Metabolic partitioning of carbon from glucose by mammalian sympathetic ganglion. J. Neurochem. 9:407–420.

    PubMed  Google Scholar 

  24. Kaufman, E. E., and Driscoll, B. F. 1992. Carbon dioxide fixation in neuronal and astroglial cells in culture. J. Neurochem. 58:258–262.

    PubMed  Google Scholar 

  25. Shank, R. P., Bennett, G. S., Freytag, S. O., and Campbell, G. L. 1985. Pyruvate carboxylase: An astrocyte-specific enzyme implieated in the replenishment of amino acid neurotransmitter pools. Brain Res. 329:364–367.

    PubMed  Google Scholar 

  26. Yu, A. C. H., Drejer, J., Hertz, L., and Schousboe, A. 1983. Pyruvate carboxylase activity in primary cultures of astrocytes and neurons. J. Neurochem. 41:1484–1487.

    PubMed  Google Scholar 

  27. Markov, A. K., Fletcher, J. A., Lehan, P. H., Hellems, H. K., and Street, D. 1986. Reduction of mortality and myocardial ischemia reperfusion injury with fructose-1,6-diphosphate (FDP). J. Am. College. Cardiol. 7:167A.

    Google Scholar 

  28. Candiani, A., Costrini, R., Cifra, E., De Santis, A. M., Lenzi, A., and Gasparetto, A. 1984. Fructose diphosphate and mean erythrocyte survival after extracorporeal circulation. Agressologie 25: 1019–1022.

    PubMed  Google Scholar 

  29. Galzigna, L., and Rigobello, M. P. 1986. Proton and potassium fluxes in rat red blood cells incubated with sugar phosphates. Experientia 42:138–139.

    PubMed  Google Scholar 

  30. Lazzarino, G., Cattani, L., Costrini, R., Mulieri, L., Candiani, A., and Galzigna, L. 1984. Increase in intraerythrocyte fructose-1,6-diphosphate. Clin Biochem. 17:42–45.

    PubMed  Google Scholar 

  31. Loreck, D. J., Galarraga, J., Van der Feen, J., Phang, J. M., Smith, B. H., and Cummins, C. J. 1987. Regulation of the pentose phosphate pathway in human astrocytes and gliomas. Met. Brain Dis. 2:31–46.

    Google Scholar 

  32. Jones, J. W., Gionis, T. A., Nichols, R. L., Markov, A., and Webb, W. R. 1980. Myocardial preservation using diphosphofructose: Energy without oxygen. Surg. Forum. 31:307–308.

    Google Scholar 

  33. Markov, A. K., Oglethorpe, N., Grillis, M., Neely, W. A., and Hellems, H. K. 1983. Therapeutic action of fructose-1,6-diphosphate in traumatic shock. World J Surg. 7:430–436.

    PubMed  Google Scholar 

  34. Markov, A. K., Terry, J., White, T., Young, D. B., Lehan, P. H., and Hellems, H. K. 1981. Protective action of fructose-1,6-diphosphate in hemorrhagic shock. Circulation II 64:231–236.

    Google Scholar 

  35. Markov, A. K., Turner, M. D., Oglethorpe, N., Neeley, W. A., and Hellems, H. K. 1981. Fructose-1,6-diphosphate: An agent for treatment of experimental endotoxin shock. Surgery 90:482–488.

    PubMed  Google Scholar 

  36. Hood, K., and Holloway, R. 1976. The significant role of fructose-1,6-diphosphate in regulatory kinetics of phosphofructokinase. FEBS Letter 68:8–14.

    Google Scholar 

  37. Speranza, M. L., Valentini, G., and Malcovati, M. 1990. Fructose-1,6-bisphosphate-activated pyruvate kinase from Escherichia coli. Nature of bonds involved in the allosteric mechanism. Eur. J. Biochem. 191:701–704.

    PubMed  Google Scholar 

  38. Kauppinen, R. A., Enkvist, K., Holopainen, I., and Akerman, K. E. O. 1988. Glucose deprivation depolarizes plasma membrane of cultured astrocytes and collapses transmembrane potassium and glutamate gradients. Neurosci. 26:283–289.

    Google Scholar 

  39. Selak, I., Skaper, S. D., and Varon, S. 1985. Pyruvate participation in the low molecular weight trophic activity for central nervous system neurons in glia-conditioned media. J. Neurosci. 5:23–28.

    PubMed  Google Scholar 

  40. Larrabee, M. G. 1980. Metabolic disposition of glucose carbon by sensory ganglia in 15-day old chicken embryos, with new dynamic models of carbohydrate metabolism. J. Neurochem. 35:210–231.

    PubMed  Google Scholar 

  41. Larrabee, M. G. 1982. [14C]Glucose metabolism in sympathetic ganglia of chicken embryos and in primary cultures of neurons and of other cells from these ganglia. J. Neurochem. 38:215–232.

    PubMed  Google Scholar 

  42. Hothersall, J. S., Baquer, N. Z., Greenbaum, A. L., and McLean, P. 1979. Alternative pathways of glucose utilization in brain. Changes in the pattern of glucose utilization in brain during development and the effect of phenazine methosulfate on the integration of metabolic routes. Arch. Biochem. Biophys. 198: 478–492.

    PubMed  Google Scholar 

  43. Zubairu, S., Hothersall, J. S., El-Hassan, A., McLean, P., and Greenbaum, A. L. 1983. Alternative pathways of glucose utilization in brain: changes in the pattern of glucose utilization and of the response of the pentose phosphate pathway to 5-hydroxytryptamine during aging. J. Neurochem. 41:76–83.

    PubMed  Google Scholar 

  44. Kirtley, M. E., and McKay, M. 1977. Fructose-1,6-diphosphate, a regulator of metabolism. Mol. Cell Biochem. 18:141–149.

    PubMed  Google Scholar 

  45. Lazzarino, G., Viola, A. R., Mulieri, L., Rotilio, G., and Mavelli, I. 1987. Prevention by fructose-1,6-bisphosphate of cardiac oxidative damage induced in mice by subchronic doxorubicin treatment. Cancer Res. 47:6511–6516.

    PubMed  Google Scholar 

  46. Markov, A. K., Finch, C. D., and Hellems, H. K. 1987. Prevention of superoxide generation and inhibition of oxygen burst in human and canine neutrophils with fructose 1–6 diphosphate (FDP). Pages 691–696,in Tsuchiya, M., Asano, M., Mishima, Y., and Oda, M. (eds.), Microcirculation, Elsevier Science Publishing Co., New York/Amsterdam.

    Google Scholar 

  47. Tavazzi, B., Cerroni, L., Di Pierro, D., Lazzarino, G., Nuutinen, M., Starnes, J. W., and Giardina, B. 1990. Oxygen radical injury and loss of high-energy compounds in anoxic and reperfused rat heart: prevention by exogenous fructose-1,6-bisphosphate. Free Rad. Res. Comms. 10:167–176.

    Google Scholar 

  48. Bristow, J., Bier, D. W., and Lange, L. G. 1987. Regulation of adult and fetal myocardial phosphofructokinase. Relief of cooperativity and competition between fructose 2,6-bisphosphate, ATP, and citrate. J. Biol. Chem. 262:2171–2175.

    PubMed  Google Scholar 

  49. Kayne, F. J. 1973. Pyruvate kinase. The Enzymes 8:353–382.

    Google Scholar 

  50. Seubert, W., Schoner, W. 1971. The regulation of pyruvate kinase. Current Topics in Cellular Regulation 3:237–267.

    Google Scholar 

  51. Hill, D. E., and Hammes, G. G. 1975. An equilibrium binding study of the interaction of fructose-6-phosphate and fructose-1,6-bisphosphate with rabbit muscle phosphofructokinase. Biochem. 14:203–213.

    Google Scholar 

  52. Bridges, R. B., Palumbo, M. P., and Wittenberger, C. L. 1975. Purification and properties of an NADP-specific 6-phosphogluconate dehydrogenase from streptococcus fecalis. J. Biol. Chem. 250:6093–6100.

    PubMed  Google Scholar 

  53. Dyson, J. E. D., and D'Orazio, R. E. 1971. 6-Phosphogluconate from sheep liver: Inhibition of the catalytic activity by fructose-1,6-diphosphate. Biochem. Biophysic. Res. Comm. 43:183–188.

    Google Scholar 

  54. Dominguez, J. E., Graham, J. F., Cummins, C. J., Loreck, D. J., Galarraga, J., Van der Feen, J., DeLaPaz, R., and Smith, B. H. 1986. Enzymes of glucose metabolism in cultured human gliomas: neoplasia is accompanied by altered hexokinase, phosphofructokinase, and glucose-6-phosphate dehydrogenase levels. Metabolic. Brain Disease 2:17–30.

    Google Scholar 

  55. McCarey, E. 1982. The biochemistry of fetal brain development and myelination. Page 278, in Jones, C. T. (ed.), The Biochemical Development of the Fetus and Neonate, Elsevier Press, New York.

    Google Scholar 

  56. Passonneau, J. V., and Lowry, D. M. 1963. P-fructokinase and the control of the citric acid cycle. Biochem. Biophys. Res. Comm. 13:372–379.

    Google Scholar 

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Author notes

  1. Judith A. Kelleher

    Present address: Department of Cell Biology, Cortex Pharmaceuticals, 15241 Barranca Blvd., Irvine, California

Authors and Affiliations

  1. Department of Neurology, University of California, 94143, San Francisco, California

    Judith A. Kelleher, Pak H. Chan & Thelma Y. Y. Chan

  2. Department of Neurosurgery, University of California, 94143, San Francisco, California

    Pak H. Chan

  3. Department of Anesthesia, School of Medicine, University of California, Box 0648, 94143, San Francisco, California

    Judith A. Kelleher & George A. Gregory

  4. Cardiovascular Research Institute, University of California, 94143, San Francisco, California

    George A. Gregory

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  3. Thelma Y. Y. Chan
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  4. George A. Gregory
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Kelleher, J.A., Chan, P.H., Chan, T.Y.Y. et al. Energy metabolism in hypoxic astrocytes: Protective mechanism of fructose-1,6-bisphosphate. Neurochem Res 20, 785–792 (1995). https://doi.org/10.1007/BF00969690

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