Abstract
Dichloroacetate (DCA) activates pyruvate dehydrogenase (PDH) by inhibiting PDH kinase. Neutralized DCA (100 mg/kg) or saline was intravenously administered to 20 to 25-day-old rats (50–75 g). Fifteen minutes later a mixture of [6−14C]glucose and [3H]fluorodeoxyglucose (FDG) was administered intravenously and the animals were sacrificed by microwave irradiation (2450 MHz, 8.0 kW, 0.6–0.8 sec) after 2 or 5 min. Brain regional rates of glucose use and metabolite levels were determined. DCA-treated rats had increased rates of glucose use in all regions studied (cortex, thalamus, striatum, and brain stem), with an average increase of 41%. Lactate levels were lower in all regions, by an average of 35%. There were no significant changes in levels of ATP, creatine phosphate, or glycogen in any brain region. Blood levels of lactate did not differ significantly between the DCA- and the saline-treated groups. Blood glucose levels were higher in the DCA group. In rats sacrificed by freeze-blowing, DCA treatment caused lower brain levels of both lactate and pyruvate. These results cannot be explained by any systemic effect of DCA. Rather, it appears that in the immature rat, DCA treatment results in activation of brain PDH, increased metabolism of brain pyruvate and lactate, and a resulting increase in brain glycolytic rate.
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Abbreviations
- DCA:
-
dichloroacetate
- FDG:
-
fluorodeoxyglucose
- PDHC:
-
pyruvate dehydrogenase complex
References
Abemayor, E., Kovachich, G. B., and Hangaard, N. (1984). Effects of dichloroacetate on brain pyruvate dehydrogenase.J. Neurochem. 42: 38–42.
Atkinson, D. E. (1968). The energy charge of the adenylate pool as a regulatory parameter. Interaction with feed back modifiers.Biochemistry 7: 4030–4034.
Baudry, M., Kessler, M., Smith, E. K., and Lynch, G. (1982). The regulation of pyruvate dehydrogenase activity in rat hippocampal slices: Effect of dichloroacetate.Neurosci. Lett. 31: 41–46.
Biros, M. H., and Dimlich, R. V. W. (1987). Brain lactate during partial global ischemia and reperfusion.Am. J. Emerg. Med. 5: 271–277.
Blomstrand, S., Hrbek, A., Karisson, K., Kjellmer, I., Lindecrantz, K., and Olsson, T. (1984). Does glucose administration affect the cerebral response to fetal asphyxia.Acta Obstet. Gynecol. Scand. 63: 345–353.
Browning, M., Baudry, M., Bennett, W. F., and Lynch, G. (1981). Phosphorylation-mediated changes in pyruvate dehydrogenase activity influence pyruvate-supported calcium accumulation by brain mitochondria.J. Neurochem. 36: 1932–1940.
Cardell, M., Koide, T., and Wieloch, T. (1989). Pyruvate dehydrogenase activity in the rat cerbral cortex following cerebral ischemia.J. Cereb. Blood Flow Metab. 9: 350–357.
Colohan, A. R. T., Welsh, F. A., Miller, E. D., and Kassell, N. F. (1986). The effect of dichloroacetate on brain lactate levels following incomplete ischemia in the hyperglycemic rat.Stroke 17: 525–528.
Crane, P. D., Pardridge, W. M., Braun, L. D., and Oldendorf, W. H. (1983). Kinetics of transport and phosphorylation of 2-fluoro-2-deoxy-D-glucose in rat brain.J. Neurochem. 40: 160–167.
Cremer, J. E., Cunningham, V. J., Pardridge, W. M., Braun, L. D., and Oldendorf, W. H. (1979). Kinetics of blood-brain barrier transport of pyruvate, lactate and glucose in suckling, weanling and adult rats.J. Neurochem. 33: 439–445.
Evans, D. B. (1983). Effects of dichloroacetate on brain tissue pyruvate dehydrogenase.J. Neurochem. 41: 1052–1056.
Finney, M. A. (1964).Statistical Method in Biological Assay, Charles Griffin, London, pp. 27–29.
Gardiner, M., Smith, M.-L., Kagstrom, E., Shohami, E., and Siesjo, B. K. (1982). Influence of blood glucose concentration on brain lactate accumulation during severe hypoxia and subsequent recovery of brain energy metabolism.J. Cereb. Blood Flow Metab. 2: 429–438.
Goldberg, N. D., Passonneau, J. V., and Lowry, O. H. (1966). Effects of changes in brain metabolism on the levels of citric acid cycle intermediates.J. Biol. Chem. 241: 3997–4003.
Hawkins, R. A., Mans, A. M., Davis, D. W., Vina, J. R., and Hibbard, L. S. (1985). Cerebral glucose use measured with [14C]glucose labeled in the 1, 2, or 6 position.Am. J. Physiol. 248: C170-C176.
Hillered, L., Siesjo, B. K., and Arfors, K.-E. (1984a). Mitochondrial response to transient forebrain ischemia and recirculation in the rat.J. Cereb. Blood Flow Metab. 4: 438–446.
Hillered, L., Ernster, L., and Siesjo, B. K. (1984b). Influence of in vitro lactic acidosis and hypercapnia on respiratory activity of isolated rat brain mitochondria.J. Cereb. Blood Flow Metab. 4: 430–437.
Kalimo, H., Rehncrona, S., Soderfeldt, B., Olsson, Y., and Siesjo, B. K. (1981). Brain lactic acidosis and ischemic cell damage. 2. Histopathology.J. Cereb. Blood Flow Metab. 1: 313–327.
Kaplan, J., Dimlich, R. V.-W., and Biros, M. H. (1987). Dichloroacetate treatment of ischemic cerebral lactic acidosis in the fed rat.Ann. Emerg. Med. 16(3): 298–304.
Katayama, Y., and Welsh, F. A. (1989). Effect of dichloroacetate on regional energy metabolites and pyruvate dehydrogenase activity during ischemia and reperfusion in gerbil brain.J. Neurochem. 52: 1817–1822.
Kuroda, Y., Toshima, K., Watanabe, T., Kobashi, H., Ito, M., Takeda, E., and Miyao, M. (1984). Effects of dichloroacetate on pyruvate metabolism in rat brain in vivo.Pediat. Res. 18: 936–938.
Lowry, O. H., and Passonneau, J. V. (1972).A Flexible System of Enzymatic Analysis, Academic Press, New York, pp. 1–291.
Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J. (1951). Protein measurement with the Folin phenol reagent.J. Biol. Chem. 193: 265–275.
Miller, A. L. (1986). Regional glucose and hydroxybutyrate use by developing rat brain.Metab. Brain Dis. 1: 53–61.
Miller, A. L., and Corddry, D. H. (1981). Brain carbohydrate metabolism in developing rats during hypercapnia.J. Neurochem. 36: 1202–1210.
Miller, A. L., and Kiney, C. A. (1981). Metabolism of [14C]fluorodeoxyglucose by rat brain in vivo.Life Sci. 28: 2071–2076.
Miller, A. L., Shamban, A. T., Corddry, D. H., and Kiney, C. A. (1982). Cerebral metabolic responses to electroconvulsive shock and their modification by hypercapnia.J. Neurochem. 38: 916–924.
Myers, R. E. (1976). Anoxic brain pathology and blood glucose.Neurology 26: 345–345.
Plum, F., Cooper, A. J. L., Kraig, R. P., Petito, C. K., and Pulsinelli, W. A. (1985). Glial cells: The silent partners of the working brain. The Thomas E. Duffy Memorial Lecture.J. Cereb. Blood Flow Metab. 5 (Suppl. 1): S1-S4.
Pulsinelli, W. A., Levy, D. E., Sigsbee, B., Scherer, P., and Plum, F. (1983). Increased damage after ischemic stroke in patients with hyperglycemia with or without established diabetes mellitus.Am. J. Med. 74: 540–544.
Rehncrona, S., Rosen, I., and Siesjo, B. K. (1981). Brain lactic acidosis and ischemic cell damage. 1. Biochemistry and neurophysiology.J. Cereb. Blood Flow Metab. 1: 297–311.
Schaffer, W. T., and Olson, M. S. (1980). The regulation of pyruvate oxidation during membrane depolarization of rat brain synaptosomes.Biochem. J. 192: 741–751.
Siesjo, B. K. (1984). Cerebral circulation and metabolism.J. Neurosurg. 60: 883–908.
Veech, R. L., Harris, R. L., Veloso, D., and Veech, E. H. (1973). Freeze-blowing: A new technique for the study of brain in vivo.J. Neurochem. 20: 183–188.
Wells, P. G., Moore, G. W., Rabin, D., Wilkinson, G. R., Oates, J. A., and Stacpoole, P. W. (1980). Metabolic effects and pharmacokinetics of intravenously administered dichloroacetate in humans.Diabetologia 19: 109–113.
Whitehouse, S., Cooper, R. H., and Randle, P. J. (1974). Mechanism of activation of pyruvate dehydrogenase by dichloroacetate and other halogenated carboxylic acids.Biochem. J. 141: 761–764.
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Miller, A.L., Hatch, J.P. & Prihoda, T.J. Dichloroacetate increases glucose use and decreases lactate in developing rat brain. Metab Brain Dis 5, 195–204 (1990). https://doi.org/10.1007/BF00997073
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DOI: https://doi.org/10.1007/BF00997073