Abstract
The effects of δ-aminolaevulinic acid (ALA), porphobilinogen (PBG), γ-aminobutyric acid (GABA), muscimol, glutamic acid and kainic acid on [3H]2-deoxy-d-glucose uptake by cultured neurons were investigated. Exposure of the cultures for 4 days, to ALA at concentrations as low as 10 μM caused a significant, dose-dependent decrease in [3H]2-deoxy-d-glucose uptake. Neither ALA nor PBG appeared to interfere directly with glucose transport into the neuron but 1 mM ALA caused an initial stimulation of [3H]2-deoxy-d-glucose uptake which increased to a maximum after 4 hr and fell to below control values after 19 hr exposure. GABA and muscimol caused similar increases in [3H]2-deoxy-d-glucose uptake but these values remained above control levels after 19 hr exposure. Glutamic acid and kainic acid caused an immediate increase in [3H]2-deoxy-d-glucose uptake which declined to mininum values after 4 hr exposure. The effect of ALA on glucose utilization in neurons may be of particular relevance to patients with acute porphyria where a genetic lesion in neural haem and haemoprotein biosynthesis is postulated to occur. ALA appeared to be more toxic to the neurons than any of the other compounds tested, possibly causing a critical depletion of energy reserves and cell death.
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Meyer, U. A., andSchmid, R. 1978. The Porphyrias. Pages 1166–1220,in Stanbury, J. B., Wyngaarden, J. B., andFredrickson, D. S. (eds.), The Metabolic Basis of Inherited Disease, McGraw-Hill, New York.
Sweeney, V. P., Pathak, M. A., andAsbury, A. K. 1970. Acute intermittent porphyria, increased ALA-synthetase activity during an acute attack. Brain 93:369–380.
Bonkowsky, H. L., Tschudy, D. P., Collins, A., Doherty, J., Bossenmaier, I., Cardinal, R., andWatson, C. J. 1971. Repression of the overproduction of porphyrin precursors in acute intermittent porphyria by intravenous infusions of hematin. Proc. Natl. Acad. Sci. 68:2725–2729.
Percy, V. A., andShanley, B. C. 1977. Porphyrin precursors in blood, urine and cerebrospinal fluid in acute porphyria. S. Afr. Med. J. 52:219–222.
Feldman, D. S., Levere, R. D., Lieberman, J. S., Cardinal, R. A., andWatson, C. J. 1971. Presynaptic neuromuscular inhibition by porphobilinogen and porphobilin. Proc. Natl. Acad. Sci. 68:383–386.
Becker, D. M., Goldstuck, N., andKramer, S. 1975. Effect of delta-aminolaevulinic acid on the resting membrane potential of frog sartorius muscle. S. Afr. Med. J. 49:1790–1792.
Dichter, H. N., Taddeini, L., Lin, S., andAyala, G. F. 1977. Delta-aminolevulinic acid. Effect of a porphyrin precursor on an isolated neuronal preparation. Brain Res. 126:189–195.
Brennan, M. J. W., andCantrill, R. C. 1979. δ-Aminolaevulinic acid is a potent agonist for GABA autoreceptors. Nature 280:514–515.
Cutler, M. G., Moore, M. R., andDick, J. M. 1980. Effects of δ-aminolaevulinic acid on contractile activity of rabbit duodenum. Eur. J. Pharmacol. 64:221–230.
Nicoll, R. A. 1976. The interaction of porphyrin precursors with GABA receptors in the isolated frog spinal cord. Life Sci. 19:521–526.
Müller, W. E., andSnyder, S. H. 1977. δ-Aminolaevulinic acid: Influences on synaptic GABA receptor binding may explain CNS symptoms of porphyria. Ann. Neurol. 2:340–342.
Percy, V. A., Lamm, M. C. L., andTaljaard, J. J. F. 1981. δ-Aminolaevulinic acid uptake, toxicity and effect on [14C]γ-aminobutyric acid uptake into neurons and glia in culture. J. Neurochem. 36:69–76.
Sokoloff, L. 1977. Relation between physiological function and energy metabolism in the central nervous system. J. Neurochem. 29:13–26.
Sokoloff, L. 1979. Mapping of local cerebral functional activity by measurement of local cerebral glucose utilization with [14]deoxyglucose. Brain 102:653–668.
Heaton, G. M., andBachelard, H. S. 1973. The kinetic properties of hexose transport into synaptosomes from guinea pig cerebral cortex. J. Neurochem. 21:1099–1108.
Diamond, I., andFishman, R. A. 1973. High-affinity transport and phosphorylation of 2-deoxy-d-glucose in synaptosomes. J. Neurochem. 20:1533–1542.
Ben-Ari, Y., Tremblay, E., Riche, D., Ghilini, G., andNaquet, R. 1981. Electrographic, clinical and pathological alterations following systemic administration of kainic acid, bicuculline or pentetrazole: Metabolic mapping using the deoxyglucose method with special reference to the pathology of epilepsy. Neuroscience 6:1361–1391.
Tschudy, D. P. 1974. Porphyrin metabolism and the porphyrias. Pages 775–824,in Bondy, P. K., andRosenberg, L. E. (eds.), Duncan's Diseases of Metabolism, W.B. Saunders, Philadelphia.
Taljaard, J. J. F., Lamm, M. C. L., Truter, L., McCarthy, B. W., Percy, V. A., andNeethling, A. C. 1981. n Ondersoek na die meganisme van δ-aminolevuliniensuur neurotoksisiteit. S. Afr. Med. J. 60:180–189.
Pettmann, B., Louis, J. C., andSensenbrenner, M. 1979. Morphological and biochemical maturation of neurones cultured in the absence of glial cells. Nature 281:378–380.
Lowry, O. H., Rosebrough, N. J., Farr, A. L., andRandall, R. J. 1951. Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193:265–275.
Percy, V. A., Lamm, M. C. L., andTaljaard, J. J. F. 1981. Effects of δ-aminolaevulinic acid, porphobilinogen, amino acids and barbiturates on calcium accumulation by cultured neurons. Biochem. Pharmacol. 30:665–666.
Wheeler, D. D., andHollingsworth, R. G. 1979. Uptake of 2-deoxy-d-glucose by cortical synaptosomes from the Long-Evans rat. J. Neurosci. Res. 4:133–145.
Bergey, G. K., andMacDonald, R. L. 1978. The porphyrin precursor delta aminolaevulinic acid diminishes amino acid responses in cultured murine spinal cord neurons. Trans. Am. Neurol. Assoc. 103:87–91.
Diemer, N. H., andSiemkowicz, E. 1980. Increased 2-deoxyglucose uptake in hippocampus, globus pallidus and substantia nigra after cerebral ischemia. Acta Neurol. Scand. 61:56–63.
Collins, R. C., McLean, M., andOlney, J. 1980. Cerebral metabolic response to systemic kainic acid: 14-C-Deoxyglucose studies. Life Sci. 27:855–862.
Wooten, G. F., andCollins, R. C. 1980. Regional brain glucose utilization following intrastriatal injections of kainic acid. Brain Res. 201:173–184.
Colombo, J. A., andSaporta, S. 1980. Increased local uptake of 2-deoxyglucose after electrochemical or direct deposition of iron into the rat brain. Exp. Neurol. 70:427–437.
Retz, K. C., andCoyle, J. T. 1980. Kainic acid lesion of mouse striatum: effects on energy metabolites. Life Sci. 27:2495–2500.
Shanley, B. C., Percy, V. A., andNeethling, A. C. 1977. Pathogenesis of neural manifestations in acute porphyria. S. Afr. Med. J. 51:458–460.
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Russell, V.A., Lamm, M.C.L. & Taljaard, J.J.F. Effects of δ-aminolaevulinic acid, porphobilinogen and structurally related amino acids on 2-deoxyglucose uptake in cultured neurons. Neurochem Res 7, 1009–1022 (1982). https://doi.org/10.1007/BF00965140
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DOI: https://doi.org/10.1007/BF00965140