Abstract
We have previously shown that in the adult rat the inhibition of brain glutamate decarboxylase (GAD) activity by pyridoxal phosphate-γ-glutamyl hydrazone (PLPGH) administration does not result in convulsions, whereas in the adult mouse intense convulsions invariably occur. In the present study we report that, surprisingly, immature rats from 2 to 20 days of age treated with PLPGH (80 mg/kg) showed generalized tonic-clonic convulsions, whereas no convulsions at all were present in 30 days-old or older rats. GAD activity, measured by enzymic determination of GABA formed in forebrain homogenates, was inhibited by about 60% at the time of convulsions in 15 days-old and younger rats, whereas the inhibition was between 40 and 50% in older animals. The addition of the coenzyme pyridoxal 5′-phosphate to the incubation medium completely reversed this inhibition. In all treated animals GABA levels were lower compared to controls. The results indicate that the susceptibility of GAD in vivo to a diminished cofactor concentration decreases with age. It seems possible that changes in the expression of enzyme forms are reflected in developmental variations in the susceptibility to seizures induced by vitamin B6 depletion, but alterations of other B6-dependent biochemical pathways cannot be discarded.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Tapia, R. 1975. Biochemical pharmacology of GABA in CNS. Pages 1–58,in Iversen, L. L., Iversen, S. D., and Snyder, S. H. (eds.) Handbook of Psychopharmacology, Vol. 4, Plenum Press, New York.
Meldrum, B. S. 1975. Epilepsy and gamma-aminobutyric acidmediated inhibition. Intern. Rev. Neurobiol. 17:1–36.
Tapia, R., Sandoval, M. E., and Contreras, P. 1975. Evidence for a role of glutamate decarboxylase activity as a regulatory mechanism of cerebral excitability. J. Neurochem. 24:1283–1285.
Lloyd, K. G. 1987. Psychopharmacology of GABAergic drugs. Pages 183–195,in Meltzer, H. Y. (ed.) Psychopharmacology: The Third Generation of Progress. Raven Press, New York.
Tapia, R., Pérez de la Mora, M. and Massieu, G. H. 1969. Correlative changes of pyridoxal kinase, pyridoxal-5′-phosphate and glutamate decarboxylase in brain, during drug-induced convulsions. Ann. N. Y. Acad. Sci. 166:257–266.
Pérez de la Mora, M., Feria-Velasco, A., and Tapia, R. 1973. Pyridoxal phosphate and glutamate decarboxylase in subcellular fractions of mouse brain and their relationship in convulsions. J. Neurochem. 20:1575–1587.
Bayoumi, R. A., and Smith, W. R. D. 1972. Some effects of dietary vitamin B6 deficiency on γ-aminobutyric acid metabolism in developing rat brain. J. Neurochem. 19:1883–1897.
Coursin, D. B. 1969. Vitamin B6 and brain function in animals and man. Ann. N.Y. Acad. Sci. 166:7–15.
Tapia, R., and Sandoval, M. E. 1971. Study on the inhibition of brain glutamate decarboxylase by pyridoxal phosphate oxime-O-acetic acid. J. Neurochem. 18:2051–2059.
Bayón, A., Possani, L. D., and Tapia, R. 1977. Kinetics of brain glutamate decarboxylase. Inhibition studies with N-(5′-phosphopyridoxyl) amino acids. J. Neurochem. 29:513–517.
Bayón, A., Possani, L. D., Tapia, M., and Tapia, R. 1977. Kinetics of brain glutamate decarboxylase. Interactions with glutamate, pyridoxal-5′ phosphate and glutamate-pyridoxal 5′-phosphate Schiff base. J. Neurochem. 29:519–525.
Covarrubias, M., and Tapia, R. 1980. Brain glutamate decarboxylase: properties of its calcium-dependent binding to liposomes and kinetics of the bound and the free enzyme. J. Neurochem. 34:1682–1688.
Erlander, M. G., and Tobin, A. J. 1991. The structural and functional heterogeneity of glutamic acid decarboxylase. A review. Neurochem. Res. 16:215–226.
Erlander, M. G., Tillakaratne, N. J. K., Feldblum, S., Patel, N., and Tobin, A. J. 1991. Two genes encode distinct glutamate decarboxylases. Neuron 7:91–100.
Martin, D. L., Martin, S. B., Wu, S. J., and Espina, N. 1991. Regulatory properties of brain glutamate decarboxylase (GAD): the apoenzyme of GAD is present principally as the smaller of the two molecular forms of GAD in brain. J. Neurosci. 11:2725–2731.
Martin, D. L., Martin, S. B., Wu, S. J., and Espina, N. 1991. Cofactor interactions and the regulation of glutamate decarboxylase activity. Neurochem. Res. 16:243–249.
Kaufman, D. L., Houser, C. R., and Tobin, A. J. 1991. Two forms of the GABA synthetic enzyme glutamate decarboxylase have distinct intraneuronal distributions and cofactor interactions. J. Neurochem. 56:720–723.
Tapia, R., and Awapara, J. 1969. Effects of various substituted hydrazones and hydrazines of pyridoxal-5′-phosphate on brain glutamate decarboxylase. Biochem. Pharmacol. 18:145–152.
Díaz-Muñoz, M. and Tapia, R. 1988. Glutamate decarboxylase inhibition and vitamin B6 metabolism in brain of cirrhotic rats chronically treated with carbon tetrachloride. J. Neurosci. Res. 20:376–382.
López-García, J. C., Bermúdez-Rattoni, F., and Tapia, R. 1990. Release of acetylcholine, γ-aminobutyrate, dopamine and glutamate, and activity of some related enzymes, in rat gustatory neocortex. Brain Res. 523:100–104.
Arias, C., Valero, H., and Tapia, R. 1992. Inhibition of brain glutamate decarboxylase activity is related to febrile seizures in rat pups. J. Neurochem. 58:369–373.
Jakoby, W. B. 1962. γ-Aminobutyrate and α-ketoglutarate assay. Pages 777–778,in Colowick, S. P. and Kaplan, N. O. (eds.) Methods in Enzymology, Vol. 5. Academic Press, New York.
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.
Tapia, R., Pasantes-Morales, H., Taborda, E., and Pérez de la Mora, M. 1975. Seizure susceptibility in the developing mouse and its relationship to glutamate decarboxylase and pyridoxal phosphate in brain. J. Neurobiol. 6:159–170.
Wood, J. D., Russell, M. P., and Kurylo, E. 1980. The γ-aminobutyrate content of nerve endings (synaptosomes) in mice after the intramuscular injection of γ-aminobutyrate-elevating agents: a possible role in anticonvulsant activity. J. Neurochem. 35:125–130.
Bond, R. W., Wyborski, R. J., and Gottlieb, D. I. 1990. Developmentally regulated expression of an exon containing a stop codon in the gene for glutamic acid decarboxylase. Proc. Nat. Acad. Sci. USA 87:8771–8775.
Guilarte, T. R., and Wagner, H. N. Jr. 1987. Increased concentrations of 3-hydroxykynurenine in vitamin B6 deficient neonatal rat brain. J. Neurochem. 49:1918–1926.
Lapin, I. P. 1981. Kynurenines and seizures. Epilepsia 22:257–265.
Pinelli, A., Ossi, C., Colombo, R., Tofanetti, O., and Spazzi, L. 1984. Experimental convulsions in rats induced by intraventricular administration of kynurenine and structurally related compounds. Neuropharmacology 23:333–337.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Massieu, L., Rivera, A. & Tapia, R. Convulsions and inhibition of glutamate decarboxylase by pyridoxal phosphate-γ-glutamyl hydrazone in the developing rat. Neurochem Res 19, 183–187 (1994). https://doi.org/10.1007/BF00966814
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00966814