Skip to main content
SpringerLink
Log in

Effect of 6-aminonicotinamide on metabolism of astrocytes and C6-glioma cells

  • Original Contributions
  • Published:
Metabolic Brain Disease Aims and scope Submit manuscript

Abstract

Brain tissue cells have been shown to use two predominant pathways for energy production. The first of these is the pentose phosphate shunt, and the second is glycolysis, followed by the TCA cycle. Inhibition of these pathways can result in a reduction of ATP, and changes in the concentration of various metabolites. In the present study, the acute and chronic effect of 6-aminonicotinamide (6-AN) (0.01, 0.02, and 0.03 mg/ml) was examined on astrocytes and C6-glioma cells. Following this treatment, glucose, lactate, glutamate, ATP, and PCr were assayed according to the procedures of Lowry and Passonneau. Our data indicated that following 15 minutes treatment of astrocytes and C6-glioma with 6AN there was no significant difference in the concentration of metabolites measured. However, following 24 hours treatment there was a significant increase in glucose concentration and significant reduction in the concentration of ATP, PCr, lactate and glutamate in both cell types. Morphological changes appeared later following 48 hours treatment with 6-AN in both cell types. Glucose accumulation can be explained by the fact that it is the precursor to both glycolysis and the pentose phosphate shunt. If these processes are inhibited, glucose will obviously accumulate and products like ATP, PCr, lactate and glutamate will decrease. Additionally, there was significant differences in concentration of glucose and lactate between astrocytes and C6-glioma cells. The significance of these differences has been discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Aikawa, H., Suzuki, K., Ito, N., Iwasaki, Y., Nonaka, I. (1984). 6-Aminonicotinamide-induced hydrocephalus in suckling mice.J. Neuropathol. Expl. Neurol. 43(5):511–521.

    CAS  Google Scholar 

  • Biddle, F.G. (1977). 6-aminonicotinamide-induced cleft palate in the mouse: The nature of the difference between the A/J and C57BL/6J strain in frequency of response and its genetic basis.Teratology 16:301–312

    Article  PubMed  CAS  Google Scholar 

  • Blakemore, W.F. (1975) Remyelination by schwann cells of axons demyelinated by intraspinal injection of 6-aminonicotinamide in the rat.J. Neurocytol. 4:745–757

    Article  PubMed  CAS  Google Scholar 

  • Buell, M.V., Lowry, O.H., Roberts, N.R., Chang, M.W., and Kapphahn, J.I. (1958). The quantitative histochemistry of the brain. V. Enzymes of glucose metabolism.J. Biol. Chem. 232:979–993

    PubMed  CAS  Google Scholar 

  • Cavanagh, J.B. (1993) Selective vulnerability in acute energy deprivation syndromes. (Review).Neuropathol. Applied Neurobiol. 19(6):461–470

    CAS  Google Scholar 

  • Chamberlain, J.G. (1970) Early neurovascular abnormalities underlying 6-aminonicotinamide (6-AN) induced congenital hydrocephalus in rats.Teratology 3:377–388

    Article  PubMed  CAS  Google Scholar 

  • Chamberlain, J.G., (1973) 6-aminonicotinamide (6-AN) induced abnormalities of the developing ependyma and choroid plexus as seen with the scanning electron microscope.Teratology 6:281–286

    Article  Google Scholar 

  • Chui, E., and Garcia J.H. (1979). Pathogenesis of 6-aminonicotinamide neurotoxicity New structural analysis. In: (H.M. Zimmermann, ed.)Progress in Neuropathology. New York: Grune and Stratton,4: 341–359

    Google Scholar 

  • Clarke, D.W., Boyd, F.T. Jr., Kappy, M.S., and Raizada, M.K. (1984). Insulin binds to specific receptors and stimulates 2-deoxy-D-glucose uptake in cultured glial cells from rat brain.J. Biol. Chem. 259:11672–11675

    PubMed  CAS  Google Scholar 

  • Coper, H., Herken, H. (1963). Schadigung des zns durch antimetaboliten des nicotinsaureamids.Dtsch. Med. Wochenschr. 88:2025–2036

    PubMed  CAS  Google Scholar 

  • DiChiro, G., DeLapaz, R.L., Brooks, R.A., Sokoloff, L., Kornblith, P.L., Smith, B.H., Petronas, N.J., Kufta, C.V., Kessler, R.M., Johnson, J.S., Manning, R.G., and Wolf, A.P. (1982). Glucose utilization of cerebral gliomas measured by (F)fluorodeoxyglucose and positron emission tomography.Neurology 32:1323–1329.

    CAS  Google Scholar 

  • Edmond, J., Ritter, W.J., Wilson, S.G., and Wilson, J.G. (1975). Inhibition of ATP synthesis associated with 6-aminonicotinamide (6-AN) teratogenesis in rat embryos.Teratology 12:233–238.

    Article  Google Scholar 

  • Edmond, J., Robbins, R.A., Bergstrom, J.D., Cole, R.A., and Vellis, J.de. (1987). Capacity for substrate utilization in oxidative metabolism by neurons, astrocytes, and oligodendrocytes from developing brain in primary cultures.J. Neurosci. Res. 18:551–561.

    Article  PubMed  CAS  Google Scholar 

  • Galarraga, J., Loreck, D.J., Graham, J.F., DeLapaz, R.L., Smith, B.H., Hallgren, D., and Cummins, C.J. (1986). Glucose metabolism in human gliomas: correspondance ofin situ andin vitro metabolic rates and altered energy metabolism.Metab. Brain Dis. 1:279–291.

    Article  PubMed  CAS  Google Scholar 

  • Geller, L.M., Cowen, D., and Wolf, A. (1966). Effect of the antimetabolite 6-aminonicotinamide on sound-induced seizures in mice.Exp. Neurol. 14:86–89.

    Article  PubMed  CAS  Google Scholar 

  • Griffiths, I.R., Kelly, P.A.T., and Grome, J.J. (1981). Glucose utilization in the central nervous system in the acute gliopathy due to 6-aminonicotinamide.Lab Invest. 44:547–52.

    PubMed  CAS  Google Scholar 

  • Herken, H., Lange, K., and Kolbe, H. (1969). brain disorders included by pharmacological blockade of the pentose shunt.Biochem. Biophys. Res. Commun. 86:83–100.

    Google Scholar 

  • Herken, H., Keller, K., Kolbe, H., Lange, K., and Schneider H. (1973). Experimetelle Myelopathie-Biochemische Grundlagen iher cellularen Pathogenese. Klin. Wschr.51:644–657

    Article  PubMed  CAS  Google Scholar 

  • Hertz, L., and Schousboe, A. (1988). Metabolism of glutamate and glutamine in neurons and astrocytes in primary cultures. In (E. Kvamme, ed)Glutamine and Glutamate in Mammals. Boca Raton. CRC Press, pp 40–45

    Google Scholar 

  • Horita, N., Oyanagi, S., Ishii, T., and Izumiyama, Y. (1978). Ultrastructure of 6-aminonicotinamide (6-AN) induced lesions in the central nervous system. I. Chromatolysis and other lesions in the cervical cord.Acta Neuropathol. (Berl.) 44:111–119

    Article  CAS  Google Scholar 

  • Horita, N., Ishii, T., and Izumiyama, Y. (1980). Ultrastructure of 6-aminonicotinamide (6-AN)-induced lesions in the central nervous system of rats. II. alterations of the nervous susceptibility with aging.Acta Neuropathol. (Berl). 49:19–27

    Article  CAS  Google Scholar 

  • Horita, N., Ishii, T., and Izumiyama, Y. (1981). Ultrastructure of 6-aminonicotinamide (6-AN)-induced lesions in the central nervous system of rats. III. Alterations of the spinal gray matter lesion with aging.Acta Neuropathol (Berl). 53:227–235

    Article  CAS  Google Scholar 

  • Iglesias-Rozas, J.R., Martin, L.F., and Iglesias, R.E. de. (1973). Histochemical changes in the spinal cord after acute poisoning with 6-aminonicotinamide.Acta Neuropathol. (Berl). 25:220–227.

    Article  CAS  Google Scholar 

  • Iglesias-Rozas, J.R., and Iglesias, R.E. de. (1974). Histochemical changes in the spinal cord after exposure to 6-aminonicotinamide.Acta Neuropathol. (Berl). 28:223–232

    Article  CAS  Google Scholar 

  • Johnson, W.J., and McColl, J.D. (1955). 6-aminonicotinamide, a potent nicotinamide antagonist.Science 122:834

    Article  CAS  PubMed  Google Scholar 

  • Kauffman, F.C., and Johnson, E.C. (1974). Cerebral energy reserves and glycolysis in neural tissue of 6-aminonicotinamide-treated mice.J. Neurobiol. 1:379–392

    Article  Google Scholar 

  • Kim, S.U., Wenger, B.S. (1973) Neurotoxic effects of 6-aminonicotinamide on cultures of central nervous tissue.Acta Neuropathol. (Berl) 26:259–264.

    Article  CAS  Google Scholar 

  • Kirsch, W.M. (1965) Substrates in glycolysis in intracranial tumors during complete ischemia.Cancer Res. 25:432–439.

    PubMed  CAS  Google Scholar 

  • Kohler, E., Barrach, H-J., and Neubert, D. (1970). Inhibition of NADP dependent oxidoreductases by the 6-aminonicotinamide analogue of NADP.FEBS Letters 6:225–228.

    Article  PubMed  Google Scholar 

  • Krum, J.M., and Rosenstein, J.M. (1993). Effect of astroglial degeneration on the blood-brain-barrier to protein in neonatal rats.Dev. Brain. Res. 74:41–50.

    Article  CAS  Google Scholar 

  • Landauer, W. (1957). Niacin antagonists and chick development.J. Exp. Zool. 136:509–530.

    Article  PubMed  CAS  Google Scholar 

  • Lange, K.H., Kolbe, K. Keller, H. and Herken, H. (1970). Der Kohlenhydrastoffwechsel des ghirns, blocked des pentose-phosphat-weges durch 6-Aminonicotinamide.Hoppe-Seylers Z. Physiol. Chem. 351:1241–1252.

    PubMed  CAS  Google Scholar 

  • Lopes-Cardozo, M., Larson, O.M., and Schousboe, A. (1986). Acetoacetate and glucose as lipid precursors and energy substrates in primary cultures of astrocytes and neurons from mouse cerebral cortex.J. Neurochem. 46:773–778.

    Article  PubMed  CAS  Google Scholar 

  • Lowry, O.H., and Passonneau, J.V. (1972). A flexible system of enzymatic analysis. Academic Press New York, pp. 129–218.

    Google Scholar 

  • Marzatico, F., Dagani, F., Curti, D., and Benzi, G. (1987). Phenobarbital and 6-aminonicotinamide effect on cerebral enzymatic activities related to energy metabolism in different rat brain areas.Neurochem. Res. 1:12:33–39

    Article  Google Scholar 

  • Matschke, G.H., and Fagerstone, K.A. (1977). Teratogenic effects of 6-aminonicotinamide in mice.J. Toxicol. Environ. Health 3:735–743.

    Article  PubMed  CAS  Google Scholar 

  • McCandless, D.W., and Scott, W.J. (1981). The effect of 6-aminonicotinamide on energy metabolism in rat embryo neural tube.Teratology 23:391–395.

    Article  PubMed  CAS  Google Scholar 

  • Meyer-Konig, E. (1973). Ultrastruktur der glia- und axonshadigung durch 6-aminonicotinamide (6-AN) am sehnerv der ratte.Acta Neuropathol. (Berl). 26:115–126.

    Article  CAS  Google Scholar 

  • Murphy, M.L., Dagg, C.P., and Karnofsky, D.A. (1957). Comparison of teratogenic chemicals in the rat and chick embryos. Pediat.19, 701.

    CAS  Google Scholar 

  • O'Sullivan, B.M., and Blakemore, W.F. (1980). Acute nicotinamide deficiency in the pig induced by 6-aminonicotinamide.Vet. Pathol. 17:748–758.

    Article  PubMed  Google Scholar 

  • Pinsky, L., and Fraser, F.C. (1959). Production of skeletal malformations in the offspring of pregnant mice treated with 6-aminonicotinamide.Biol. Neonate 1:106–112.

    Article  CAS  Google Scholar 

  • Pinsky, L., and Fraser, F.C. (1960) Congenital malformations after a two-hour inactivation of nicotinamide in pregnant mice.Brit. Med. J. 2:195.

    Article  PubMed  CAS  Google Scholar 

  • Ritter, E.J., Scott, W.J., and Wilson, J.G. (1975). Inhibition of ATP synthesis associated with aminonicotinamide teatogenesis in rat embryos. Teratology12:233–238.

    Article  PubMed  CAS  Google Scholar 

  • Schardein, J.L., Woosley, E.T., Peltzer, M.A., and Kaump, D.H. (1967). Congenital malformations induced by 6-aminonicotinamide in rabbit kits.Exp. Mol. Pathol. 6:335–346.

    Article  PubMed  CAS  Google Scholar 

  • Schneider, H., and Cervos-Navarro, J. (1974). Acute gliopathy in spinal cord and brain stem induced by 6-aminonicotinamide.Acta Neuropathol. (Berl). 27:1123.

    Article  Google Scholar 

  • Schneider, H., and Coper, H. (1968). Morphologische befunde am zentralnervensystem der ratte nach vergiftung mit antimetaboliten des nicotinamides und einem chinolinderivat.Arch. Psychiat. Nervenkr. 211:138–154

    Article  PubMed  CAS  Google Scholar 

  • Schochet, S.S. Jr. (1970). Pathogenesis of 6-aminonicotinamide neurotoxicity.VIth International Congress of Neuropathology Proceedings. Paris: Masson, 89–90.

    Google Scholar 

  • Schotland, D.L., Cowen, D., Geller, L.M., and Wolf, A. (1965). A histopathological study of the effects of an antimetabolite, 6-aminonicotinamide, on the lumbar spinal cord of the adult rat.J. Neuropathol. Exp. Neurol. 24:97–107

    PubMed  CAS  Google Scholar 

  • Schousboe, A., Drejer, J., Hertz, L. (1988). Uptake and release of glutamate and glutamine in neurons and astrocyte in primary cultures. In (E. Kvamme, ed)Glutamine and Glutamate in Mammals Boca Raton. CRC Press, pp 21–38

    Google Scholar 

  • Siegel, S. (1956). Non-parametric statistics for the behavioral scientist. McGraw-Hill, New York.

    Google Scholar 

  • Smith, P.K., Krohn, R.I., Hermanson, G.T., Mallia, A.K., Gartner, F.H., Provenzano, M.D., Fujimoto, E.K., Goeke, N.M., Olson, B.J., and Klenk, D.C. (1985). Measurement of protein using bicinchoninic acid.Anal. Biochem. 150:76–85.

    Article  PubMed  CAS  Google Scholar 

  • Sotelo, C. (1967). Cerebellar neuroglia: morphological and histochemical aspects.Prog. Brain Res. 25: 226–250.

    PubMed  CAS  Google Scholar 

  • Sotelo, C., and Rio, J.P. (1980). Cerebellar malformation obtained in rats by early postnatal treatment with 6-aminonicotinamide. Role of neuron-glia interactions in cerebellar development.Neuroscience 5:1737–1759

    Article  PubMed  CAS  Google Scholar 

  • Sternberg, S.S., and Philips, F.S. (1958). 6-aminonicotinamide and acute degenerative changes in the central nervous system.Science 127:644–646

    Article  PubMed  CAS  Google Scholar 

  • Westergaard, N., Sonnewald, U., and Schousboe, A. (1995). Metabolic trafficking between neurons and astrocytes: The glutamate/glutamine cycle revisited.dev. Neurosci. 17:203–211.

    PubMed  CAS  Google Scholar 

  • Wolf, A., and Cowen, D. (1959). Pathological changes in the central nervous system produced by 6-aminonicotinamide.Bull. N. Y. Acad. Med. 35:814–817

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cell Biology and Anatomy, Finch University of Health Sciences/The Chicago Medical School, 3333 Green Bay Road, 60064, North Chicago, IL

    Nasrin Haghighat & David W. McCandless

Authors
  1. Nasrin Haghighat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David W. McCandless
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Haghighat, N., McCandless, D.W. Effect of 6-aminonicotinamide on metabolism of astrocytes and C6-glioma cells. Metab Brain Dis 12, 29–45 (1997). https://doi.org/10.1007/BF02676352

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02676352

Key words

Search

Navigation