Abstract
The antiepileptic drug Na+-valproate (VPA) is a broadspectrum anticonvulsant. It has been proposed to be involved in the inhibitory mechanisms of GABA-ergic systems. In this study, transport of the drug and possible influence on the GABA uptake were investigated in primary astroglial cell cultures from newborn rat cerebral cortex. The results show a Na+ and K+ independent high affinity uptake for VPA, withK m andV max not significantly different from those observed for the GABA uptake. In the presence of the drug, the Km-value of the GABA uptake increased. The GABA uptake inhibitors guvacine, (RS)-Cis-4-OH-nipecotic acid and 4,5,6,7-tetrahydroisoxazolo (4,5-c) pyridin-3-ol (THPO) did not influence upon the uptake of VPA, suggesting a transport mechanism for the drug, separated from the GABA uptake carrier.
Similar content being viewed by others
References
Aman, M.G., Werry, J.S., Paxton, J.W., and Turbott, S.H. 1987. Effects of Sodium Valproate on Psychomotor Performance in Children as a Function of Dose, Fluctuations in Concentration, and Diagnosis. Epilepsia. 28:115–124.
Gram, L., and Bentsen, D. 1985. Valproate: an updated review. Acta Neurol. Scand. 72:129–139.
Macdonald, R.L., and McLean, M.J. 1986. Anticonvulsant Drugs: Mechanisms of Action. Pages 713–736.in (A.V. Delgado-Escueta, A.A. Ward Jr., D.M. Woodbury, and R.J. Porter eds.) Adv. Neurol. vol 44, Raven Press, New York.
Godin, Y., Heiner, L., Mark, J., and Mandel, P. 1969. Effects of di-n-propylacetate, an anticonvulsant compound on GABA metabolism. J. Neurochem. 16:869–873.
Gram, L., Larsson, O.M., Johnsen, A.H., and Schousboe, A. 1988. Effects of valproate, vigabatrin and aminooxyacetic acid on release of endogenous and exogenous GABA from cultured neurons. Epilepsy Res. 2:87–95.
Preisendörfer, U., Zeise, M.L., and Klee, R. 1987. Valproate enhances inhibitory postsynaptic potentials in hippocampal neurons in vitro. Brain Res. 435:213–219.
Hackman, J.C., Grayson, V., and Davidoff, R.A. 1981. The presynaptic effects of valproic acid in the isolated frog spinal cord. Brain Res. 220:269–285.
VanDongen, A.M.J., Van Erp, M.G., and Voskuyl, R.A. 1986. Valproate reduces excitability by blockage of sodium and potassium conductance. Epilepsia. 27:177–182.
Larsson, O.M., Gram, L., Schousboe, I., and Schousboe, A. 1986. Differential effect of gamma-vinyl GABA and valproate on GABA-transaminase from cultured neurons and astrocytes Neuropharmacology. 25:617–625.
Martin, M.L., and Regan, C.M. 1988. The anticonvulsant sodium valproate specifically induces the expression of a rat glial heat shock protein which is identified as the collagen type IV receptor. Brain Res. 459:131–137.
Hansson, E., Eriksson, P., and Nilsson, M. 1985. Amino acid and monoamine transport in primary astroglial cultures from defined brain regions. Neurochem. Res. 10:1335–1341.
Hertz, L. 1979. Functional interactions between neurons and astrocytes I. Turnover and metabolism of putative amino-acid transmitters. Progr. Neurobiol. 13:277–323.
Sellström, Å., and Hamberger, A. 1975. Neuronal and glial systems for γ-aminobutyric acid transport. J Neurochem. 24:847–852.
Waltz, W., and Hertz, L. 1983. Functional interactions between neurons and astrocytes II. Potassium homeostasis at the cellular level. Progr. Neurobiol. 20:133–183.
Hansson, E., Rönnbäck, L., Persson, L.I., Lowenthal, A., Noppe, M., Alling, C., and Karlsson, B. 1984. Cellular composition of primary cultures from cerebral cortex, striatum, hippocampus, brain stem and cerebellum. Brain Res. 300:9–18.
Hansson, E., Isacsson, H., and Sellström, Å. 1984. Characteristics of dopamine and GABA transport in primary cultures of astroglial cells. Acta Phys. Scand. 121:333–341.
Lowry, O.H., Rosebrough, N.J., Farr, A.L., and Randall, R.J. 1951. Protein measurements with the Folin Phenol reagent. J. Biol. Chem. 193:265–275.
Krogsgaard-Larsen, P., Falch, E., Larsson, O.M., and Schousboe, A. 1987. GABA uptake inhibitors: relevance to antiepileptic drug research. Epilepsy Res. 1:77–93.
Schousboe, A., Hjeds, H., Engler, J., Krogsgaard-Larsen, P. and Wood, J.D. 1986. Tissue distribution, metabolism, anticonvulsant efficacy and effect on brain amino acid levels of the glia selective γ-aminobutyric acid transport inhibitor 4,5,6,7-tetrahydroisoxazolo (4,5-c) pyridin-3-ol in mice and chicks. J. Neurochem. 47:758–763.
Aly, M.I., and Abdel-Latif, A.A. 1980. Studies on distribution and metabolism of valproate in rat brain, liver and kidney. Neurochem. Res. 5:1231–1242.
Frey, H.H., and Löscher, W. 1978. Distribution of valproate across the interface between blood and cerebrospinal fluid. Neuropharmacology. 17:637–642.
Cornford, E.M., Diep, C.P., and Pardridge. 1985. Blood-brain barrier transport of valproic acid. J. Neurochem. 44:1541–1550.
Deuticke, B. 1989. Monocatboxylate transport in red blood cells: kinetics and chemical modification. Meth. Enzymol. 173:300–329.
Bolli, R., Nalecz, K.A., and Azzi, A. 1989. Monocarboxylate and α-ketoglutarate carriers from bovine heart mitochondria. J. Biol. Chem. 264:18024–18030.
Balcar, V.J., Mark, J., Borg, J., and Mandel, P. 1979. High affinity uptake of γ-aminobutyric acid in cultured glial and neuronal cells. Neurochem. Res. 4:339–354.
Schousboe, A., Hertz, L., and Svenneby, G. 1977. Uptake and metabolism of GABA in astrocytes cultured from dissociated mouso brain hemispheres. Neurochem. Res. 2:217–229.
Löscher, W., and Schwartz-Porsche, D. 1986. Low levels of γ-aminobutyric acid in cerebrospinal fluid of dogs with epilepsy J. Neurochem. 46:1322–1325.
Ribak, C.E. 1985. Axon terminals of GABA-ergic Chandelier cells are lost at epileptic foci. Brain Res. 326:251–260.
Roberts, E. 1984. GABA Related Phenomena, Models of Nervous System Function, and Seizures. Ann. Neurol. 16(suppl.):77–89.
Peters, A., Palay, S.L., and Webster, H. de F. (eds.). 1976. The fine structure of the nervous system: the Neurons and Supporting cells. W.B. Saunders company, Philadelphia, London, Toronto.
Pope, A. 1978. Dynamic Properties of Glia Cells, Pages 13–20,in Schoffeniels, E., Franck, G., Tower, D.B., and Hertz, L. (eds.) Pergamon Press, Oxford and New York.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Nilsson, M., Hansson, E. & Rönnbäck, L. Transport of valproate and its effects on GABA uptake in astroglial primary culture. Neurochem Res 15, 763–767 (1990). https://doi.org/10.1007/BF00968551
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00968551