Skip to main content
Log in

The specific protective effect of diazepam and valproate against isoniazid-induced seizures is not correlated with increased GABA levels

  • Original Papers
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Summary

Amino acid concentrations were measured in the cortex, cerebellum and hippocampus of the mouse brain before and during seizures induced by isoniazid (250 mg/kg i.p.), an inhibitor of L-glutamate-1-decarboxylase (EC 4.1.1.15: GAD). Valproate sodium and diazepam dose-dependently delay the onset of convulsive fits caused by isoniazid. However, neither diazepam nor valproate prevented the decrease in GABA concentrations produced by isoniazid alone. Also, these antiepileptic drugs did not modify the rate of GABA depletion elicited by isoniazid. These results, observed in four different brain structures, strengthen those first obtained withβ-vinyllactic acid, another inhibitor of GAD.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  • Anlezark, G., Horton, R. W., Meldrum, B. S., Sawaya, M. C. B.: Anticonvulsant action of ethanolamine-o-sulphate and di-n-propylacetate and the metabolism ofγ-aminobutyric acid (GABA) in mice with audiogenic seizures. Biochem. Pharmacol.25, 413–417 (1976).

    Google Scholar 

  • Benson, J. R., Hare, P. E.: o-Phthaldehyde: Fluorogenic detection of primary amines in the picomole range. Comparison with fluorescamine and ninhydrin. Proc. Natl. Acad. Sci. U.S.A.72, 619–622 (1975).

    PubMed  Google Scholar 

  • Bernasconi, R., Maître, L., Martin, P., Raschdorf, F.: 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, 57–66 (1982).

    PubMed  Google Scholar 

  • Bernasconi, R., Schmutz, M., Martin, P., Hauser, K.: GABA hypothesis for the mechanism of action of antiepileptic drugs: its usefulness and limitations. In: Neurotransmitters, Seizures and Epilepsy II (Fariello, R. G., Morselli, P. L., Lloyd, K. G., Quesney, L. F., Engel, J. jr., eds.). New York: Raven Press. 1984 a (in press).

    Google Scholar 

  • Bernasconi, R., Bencze, W., Hauser, K., Klein, M., Martin, P., Schmutz, M.: Protective effects of diazepam and valproate onβ-vinyllactic acid-induced seizures. Neurosci. Lett.47, 339–344 (1984 b).

    PubMed  Google Scholar 

  • Bernasconi, R., Hauser, K., Martin, P., Schmutz, M.: Biochemical aspects of the mechanism of action of valproate. In: Anticonvulsants in Affective Disorders (Emrich, H. M., Okuma, T., Mueller, A. A., eds.), pp. 14–32. Amsterdam: Excerpta Medica. 1984 c.

    Google Scholar 

  • Chapman, A. G., Riley, K., Evans, M. C., Meldrum, B. S.: Acute effects of sodium valproate andγ-vinyl GABA on regional amino acid metabolism in the rate brain: Incorporation of 2-[14C]glucose into amino acids. Neurochem. Res.7, 1089–1105 (1982).

    PubMed  Google Scholar 

  • Chapman, A. G., Westerberg, E., Premachandra, M., Meldrum, B. S.: Changes in regional neurotransmitter amino acid levels in rat brain during seizures induced by L-allylglycine, bicuculline and kainic acid. J. Neurochem.43, 62–70 (1984).

    PubMed  Google Scholar 

  • Costa, E.: Benzodiazepines and neurotransmitters. Arzneimittelforsch.30, 858–861 (1980).

    PubMed  Google Scholar 

  • Costa, E., Giudotti, A.: Molecular mechanisms in the receptor action of benzodiazepines. Annu. Rev. Pharmacol. Toxicol.19, 531–545 (1979).

    PubMed  Google Scholar 

  • Costa, E., Guidotti, A., Mao, C. C.: Evidence for involvement of GABA in the action of benzodiazepines: Studies on rat cerebellum. In: Mechanism of Action of Benzodiazepines (Costa, E., Greengard, P., eds.), pp. 113–130. New York: Raven Press. 1975 a.

    Google Scholar 

  • Costa, E., Guidotti, A., Mao, C. C., Suria, A.: New concepts on the mechanism of action of benzodiazepines. Life Sci.17, 167–185 (1975 b).

    PubMed  Google Scholar 

  • Delini-Stula, A.: Differential effects of baclofen and muscimol on behavioural responses implicating GABA-ergic transmission. In: GABA-Neurotransmitters: Pharmacochemical, Biochemical and Pharmacological Aspects (Krogsgaard-Larsen, P., Scheel-Krueger, J., Kofod, H., eds.), pp. 482–499. Copenhagen: Munksgaard. 1979.

    Google Scholar 

  • Fowler, L. J., Beckford, J., John, R. A.: An analysis of the kinetics of the inhibition of rabbit brainγ-aminobutyrate aminotransferase by sodium n-dipropylacetate and some other simple carboxylic acids. Biochem. Pharmacol.24, 1267–1270 (1975).

    PubMed  Google Scholar 

  • Guidotti, A.: Synaptic mechanisms in the action of benzodiazepines. In: Psγ-chopharmacology: A generation of progress (Lipton, M. A., DiMascio, A., Killam, K. F., eds.), pp. 1349–1357. New York: Raven Press. 1978.

    Google Scholar 

  • Hollander, M., Wotke, D. A.: Nonparametric Statistical Methods. New York: J. Wiley. 1973.

    Google Scholar 

  • Lindgren, S., Andén, N. E.: On the use of enzyme inhibitors to study the synthesis and utilization of brain GABA. Acta Pharmacol. Toxicol.55, 41–49 (1984).

    Google Scholar 

  • Loescher, W., Frey, H. H.: Effect of convulsant and anti-convulsant agents on level and metabolism ofγ-aminobutyric acid in mouse brain. Naunyn-Schmiedeberg's Arch. Pharmacol.296, 263–269 (1977).

    Google Scholar 

  • Lust, W. D., Kupferberg, H. J., Yonekawa, W. D., Penry, J. K., Passonneau, J. V., Wheaton, A. B.: Changes in brain metabolites induced by convulsants or electroshock: Effects of anticonvulsants agents. Mol. Pharmacol.14, 347–356 (1978).

    PubMed  Google Scholar 

  • Mao, C. C., Marco, E., Revuelta, A., Bertilsson, L., Costa, E.: The turnover rate ofγ-aminobutyric acid in the nuclei of telencephalon: Implications in the pharmacology of antipsychotics and a minor tranquilizer. Biol. Psychiatry12, 359–371 (1977).

    PubMed  Google Scholar 

  • McCandless, D. W., Feussner, G. K., Lust, W. D., Passonneau, J. V.: Metabolite levels in brain following experimental seizures: The effects of isoniazid and sodium valproate in cerebellar and cerebral cortical layers. J. Neurochem.32, 755–760 (1979).

    PubMed  Google Scholar 

  • Meldrum, B. S.: Epilepsy andγ-aminobutyric acid-mediated inhibition. Int. Rev. Neurobiol.17, 1–35 (1975).

    PubMed  Google Scholar 

  • Moore, S., Spackman, D. H., Stein, W. H.: Chromatography of amino acids on sulfonated polystyrene resins. Anal. Chem.30, 1185–1190 (1958).

    Google Scholar 

  • Roberts, E., Kuriyama, K.: Biochemical-physiological correlations in studies of theγ-aminobutyric acid system. Brain Res.8, 1–35 (1968).

    PubMed  Google Scholar 

  • Schmid, R., Karobath, M.: Specific and sensitive method for the determination ofγ-aminobutyric acid using gas chromatography with electron-capture or mass fragmentographic detection. J. Chromatogr.139, 101–109 (1977).

    PubMed  Google Scholar 

  • Simler, S., Ciesielski, L., Maître, M., Randrianarisoa, H., Mandel, P.: Effect of sodium n-dipropylacetate on audiogenic seizures and brainγ-aminobutyric acid level. Biochem. Pharmacol.22, 1701–1708 (1973).

    PubMed  Google Scholar 

  • Storm-Mathisen, J.: Distribution of the components of the GABA system in neuronal tissue: Cerebellum and hippocampus-Effects of axotomy. In: GABA in Nervous System Function (Roberts, E., Chase, T. N., Tower, D. B., eds.), pp. 149–168. New York: Raven Press. 1976.

    Google Scholar 

  • Tutschek, R., Meier, K. D., Gruening, F., Stubba, W.: Amino acid analysis of physiological fluids by a single column programme based on stepwise elution with lithium citrate. J. Chromatogr.139, 211–214 (1977).

    PubMed  Google Scholar 

  • Winer, B. J.: Statistical principles in experimental design. New York: McGraw-Hill. 1971.

    Google Scholar 

  • Wood, J. D., Peesker, S. J.: A correlation between changes in GABA metabolism and isonicotinic acid hydrazide-induced seizures. Brain Res.45, 489–498 (1972).

    PubMed  Google Scholar 

  • Woodbury, D. M.: Convulsant drugs: Mechanism of action: In: Antiepileptic Drugs. Mechanism of Action (Glaser, G. H., Penry, J. K., Woodbury, D. M., eds.), pp. 249–303. New York: Raven Press. 1980.

    Google Scholar 

  • Wu, J. Y., Su, Y. Y. T., Lam, D. M. K., Brandon, C.: Properties and kinetics of L-glutamate decarboxylase. In: Amino Acid Neurotransmitters (DeFeudis, F. V., Mandel, P., eds.), pp. 499–508. New York: Raven Press. 1981.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Additional information

This work is part of Miss Klein's thesis (Strasbourg, 1985).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bernasconi, R., Klein, M., Martin, P. et al. The specific protective effect of diazepam and valproate against isoniazid-induced seizures is not correlated with increased GABA levels. J. Neural Transmission 63, 169–189 (1985). https://doi.org/10.1007/BF01252616

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01252616

Keywords

Navigation