Effect of Valproate on In Vivo GABA-Turnover

  • Raymond Bernasconi
  • Markus Schmutz
  • Pierre Martin
  • Kathleen Hauser


Valproate is an effective antiepileptic drug in animals (1) and man (2). Valproate raises brain GABA levels and biochemical studies have shown that it weakly inhibits the different enzymes related to the GABA catabolism, viz., 4-aminobutyrate: 2-oxoglutarate ami- transferase (E.C.; GABA-T) (3) and succinic semialdehyde dehydrogenase (E.C. (4). It has been suggested that blockade of GABA catabolism is responsible for the increased GABA levels. On the other hand it has been proposed that valproate may enhance GABA synthesis by increasing L-glutamate-l-decarboxy- lase (E.C.; GAD) activity and that this is the cause for the rise in GABA levels (5). The precise mechanism responsible for the GABA elevating effect of valproatein vivo remains to be clarified. The measure of GABA levels after inhibition of GABA-T and GAD could help to distinguish between two hypotheses. In this report, two major issues are addressed:
  1. a)

    What is the action of valproate on GABA turnover rate?

  2. b)

    Is the protection by valproate against convulsions induced by a reduction of GABA content, dependent on a normalization of GABA concentration?



Sodium Valproate Gaba Level Gaba Concentration Gaba Content Aminooxyacetic Acid 
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  1. 1.
    S. Simler, L. Ciesielski, M. Maitre, H. Randrianarisoa, and P. Mandel, Effect of sodium n-dipropyl- acetate on audiogenic seizures and brain gamma-ami- nobutyric acid level,Biochem. Pharmac. 22: 1701 (1973).CrossRefGoogle Scholar
  2. 2.
    D. Simon, and J.K. Penry, Sodium Di-N-propylacetate (DPA) in the treatment of epilepsy,Epilepsia 16: 549 (1975).PubMedCrossRefGoogle Scholar
  3. 3.
    P. Mandel, S. Simler, and L. Ciesielski, Epilepsy: basic biochemistry and pharmacology,in Psychopharmacology of anticonvulsants, M. Sandler, ed., Oxford University Press, Oxford, New York (1982).Google Scholar
  4. 4.
    G. Anlezard, R.W. Horton, B.S. Meldrum, and C.B. Sawaya, Anticonvulsant action of ethanolamine-o-sulphate and Di-n-propylacetate and the metabolism of gamma-aminobutyric acid (GABA) in mice with audiogenic seizures,Biochem Pharmac. 25: 413 (1976).CrossRefGoogle Scholar
  5. 5.
    W. Löscher, Valproate induced changes in GABA metabolism at the subcellular level,Biochem. Pharmac. 30: 1364 (1981).CrossRefGoogle Scholar
  6. 6.
    R. Bernasconi, L. Maitre, P. Martin, and F. Raschdorf, The use of inhibitors of GABA-transaminase for the determination of GABA turnover in mouse brain regions: an evaluation of aminooxyacetic acid and gabaculine,J. Neurochem. 38: 57 (1982).PubMedCrossRefGoogle Scholar
  7. 7.
    R. Schmid, and M. Karobath, Specific and sensitive method for the determination of gamma-aminobutyric acid using gas chromatography with electron-capture or mass fragmentographic detection,J. Chromat. 139: 101 (1977).CrossRefGoogle Scholar
  8. 8.
    Z.W. Hall, and E.A. Kravitz, The metabolism of gamma-aminobutyric acid (GABA) in the lobster nervous system,J. Neurochem. 14: 45 (1967).PubMedCrossRefGoogle Scholar
  9. 9.
    S.H. Wilson, B.K. Schrier, J.L. Farber, E.J. Thompson, R.N. Rosenberg, A.J. Blume, and M.W. Nirenberg, Markers for gene expression in cultured cells from the nervous system,J. biol. Chem. 247: 3159 (1972).PubMedGoogle Scholar
  10. 10.
    O.H. Lowry, N.J. Rosebrough, A.L. Farr, and R.J. Randall, Protein measurement with the Folin phenol reagent,J. biol. Chem. 193: 265 (1951).PubMedGoogle Scholar
  11. 11.
    R.W. Horton, The role of 2-keto-4-pentenoic acid in seizures induced by allylglycine,Biochem. Pharmac. 27: 1471 (1978).CrossRefGoogle Scholar
  12. 12.
    D.F. Reingold, and M. Orlowski, Inhibition of brain glutamate decarboxylase by 2-keto-4-pentenoic acid, a metabolite of allylglycine,J. Neurochem. 32: 907 (1979).PubMedCrossRefGoogle Scholar
  13. 13.
    W. Löscher, and H.H. Frey, Effect of convulsant and anticonvulsant agents on level and metabolism of gamma-aminobutyric acid in mouse brain,Naunyn-Schmiedebergs Arch, exp. Path. Pharmak. 296: 363 (1977).Google Scholar
  14. 14.
    P.J. Schechter, Y. Tranier, and J. Grove (1978), Effect of n-dipropylacetate on amino acid concentrations in mouse brain: correlations with anticonvulsant activity,J. Neurochem. 31: 1325 (1978).Google Scholar
  15. 15.
    A.G. Chapman, K. Riley, M.C. Evans, and B.S. Meldrum, Acute effects of sodium valproate and gamma- vinyl GABA on regional amino acid metabolism in the rat brain: incorporation of 2-(14C)glucose into amino acids,Neurochem. Res. 7: 1089 (1982).PubMedCrossRefGoogle Scholar
  16. 16.
    J.E. Cremer, G.S. Sarna, H.M. Teal, and V.J. Cunningham, Amino acid precursors: their transport into brain and initial metabolism,in Amino acids as chemical transmitters, F. Fonnum, ed., Plenum Press, New York (1978).Google Scholar

Copyright information

© Plenum Press, New York 1985

Authors and Affiliations

  • Raymond Bernasconi
    • 1
  • Markus Schmutz
    • 1
  • Pierre Martin
    • 1
  • Kathleen Hauser
    • 1
  1. 1.Research Laboratories Pharmaceuticals DivisionCIBA-GEIGY LtdBasleSwitzerland

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