Excitatory Amino Acids: Approaches to Rational Anticonvulsant Therapy

  • B. S. Meldrum
  • A. G. Chapman
  • L. M. Mello
  • M. H. Millan
  • S. Patel
  • L. Turski

Abstract

In recent years, enhancement of inhibitory transmission has come to be considered the most important rational approach to the design of novel anticonvulsant drugs (Meldrum, 1983). This has led to clinical trials involving several novel compounds, designed to enhance GABA-mediated inhibition such as Progabide and Vigabatrin. The alternative approach of seeking compounds that impair excitatory transmission has only recently attracted attention. It might be thought that impairing excitatory transmission is unlikely to suppress epileptic activity selectively while leaving normal function intact. However, as will be explained below, there are reasons why it may be possible to act selectively on the sustained abnormal discharge of epilepsy.

Keywords

Adenosine Diazepam Homocysteine Clonidine Salbutamol 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Anderson, E., Baudry, M., Lynch, G. and Morris R.G.M. (in Press). Selective impairment of learning and blockade of long-term potentiation by an N-methyl-Daspartate receptor antagonist, APV-5. Physiol. Soc.__, 38P.Google Scholar
  2. Ault, B. and Nadler, J.V. (1983). Anticonvulsant like actions of baclofen in the rat hippocampal slice. Brit. J. Pharmacol. 78, 701–708.CrossRefGoogle Scholar
  3. Baba, A., Okumura, S., Mizuo, H. and Iwata, H.(1983). Inhibition by diazepam and?-aminobutyric acid of depolarization-induced release of [14C]cysteine sulfinate and [3H]glutamate in rat hippocampal slices. J. Neurochem. 40, 280–4.PubMedCrossRefGoogle Scholar
  4. Barraco, R.A., Swanson, T.H., Phillis, J.W. and Berman, R.F. (1984). Anticonvulsant effects of adenosine analogues on amygdaloid-kindled seizures in rats. Neurosci. Lett., 46, 317–322.PubMedCrossRefGoogle Scholar
  5. Beaton, T. (1961). The inhibition by acetazoleamide of renal phosphate activated glutaminase in rats. Can. J. Biochem. Physiol. 39, 663–6.PubMedCrossRefGoogle Scholar
  6. Bowery, N.G., Hill, D.R., Hudson, A.L., Doble, A., Middlemiss, D.N., Shaw, J. and Turnbull, M. (1980). (-)Baclofen decreases neurotransmitter release in the mammalian CNS by an action of a novel GABA receptor. Nature 362, 92–4.CrossRefGoogle Scholar
  7. Chapman, A.G., Riley, K., Evans, M.C. and Meldrum, B.S. (1982). Acute effects of sodium valproate and?-vinyl GABA on regional amino acid metabolism in the rat brain. Neurochem. Res. 7, 1089.PubMedCrossRefGoogle Scholar
  8. Chapman, A.G., Meldrum, B.S. and Mendes, E. (1983a). Acute anticonvulsant activity of structural analogues of valproic acid and changes in brain GABA and aspartate content. Life Sci. 32, 2023–31.PubMedCrossRefGoogle Scholar
  9. Chapman, A.G., Collins, J.F., Meldrum, B.S. Westerberg, E. (1983b). Uptake of a novel anticonvulsant compound, 2-amino-7-phosphono-(4,53H)-heptanoic acid, into mouse brain. Neurosci. Lett. 37, 75–80.PubMedCrossRefGoogle Scholar
  10. Chapman, A.G., Croucher, M.J. and Meldrum, B.S. (1984). Evaluation of anticonvulsant drugs in DBA/2 mice with sound-induced seizures. Arzneimitt. Forsch. 34., 1261–1264.Google Scholar
  11. Chapman, A.G., Hart, G.P., Meldrum, B.S., Turski, L. and Watkins, J.C. (1985). anticonvulsant activity of two novel piperazine derivatives with potent kainate antagonist activity. Neurosci. Lett., 55, 325–330.PubMedCrossRefGoogle Scholar
  12. Chung, S.H., Johnson, M.S. (1984). Studies on sound-induced epilepsy in mice. Proc. Roy. Soc B., 221, 145–168.CrossRefGoogle Scholar
  13. Collingridge, G.L., Kehl, S.J. and McLennan, H. (1983). The antagonism of amino acid-induced excitations of rat hippocampal CA1 neurones in vitro. J. Physiol. (Lond)., 334, 19–31.PubMedCentralCrossRefGoogle Scholar
  14. Collins, G.G.S. (1981). The effects of chlordiazepox on synaptic transmission and amino acid neurotransmitter release in slices of rat olfactory cortex. Brain Res., 224, 389.PubMedCrossRefGoogle Scholar
  15. Collins, G.G.S., Anson, J. and Surtees, L. (1983). Presynaptic kainate and N-methyl-D-aspartate receptors regulate excitatory amino acid release in the olfactory cortex. Brain Res., 265, 157–159.PubMedCrossRefGoogle Scholar
  16. Collins, J.F., Dixon, A.J., Badman, G., De Sarro, D., Chapman, A.G. Hart, G.P. and Meldrum, B.S. (1984). Kainic acid derivatives with anticonvulsant activity. Neurosci. Lett., 51, 371–376.PubMedCrossRefGoogle Scholar
  17. Croucher, M.J., Collins, J.F. and Meldrum, B.S. (1982). Anticonvulsant action of excitatory amino acid antagonists. Science 216, 899–901.PubMedCrossRefGoogle Scholar
  18. Croucher, M.J., Meldrum, B.S., Jones, A.W. and Watkins, J.C. (1984a).?-D-Glutamylaminomethyl-sulphonic acid (GAMS), a kainate and quisqualate antagonist, prevents sound-induced seizures in DBA/2 mice. Brain Res. 322, 111–114.PubMedCrossRefGoogle Scholar
  19. Croucher, M.J., Meldrum, B.S. and Collins, J.F. (1984b). Anticonvulsant and proconvulsant properties of a series of structural isomers of piperidine decarboxylic acid. Neuropharmacol., 23, 467–472.CrossRefGoogle Scholar
  20. Czuczwar, S.J., Meldrum, B. (1982). Protection against chemically induced seizures by 2-amino-7-phosphonoheptanoic acid. Eur. J. Pharmacol. 83, 335–338.PubMedCrossRefGoogle Scholar
  21. Davies, J., Evans, R.H., Jones, A.W., Smith, D.A.S. and Watkins, J.C. (1982). Differential activation and blockade of excitatory amino acid receptors in the mammalian and amphibian central nervous system. Comp. Biochem. Physiol. 72C, 211–224.Google Scholar
  22. Dolphin, A.C. (1982). Noradrenergic modulation of glutamate release in the cerebellum. Brain Res., 252, 111–116.PubMedCrossRefGoogle Scholar
  23. Dolphin, A.C. and Archer, E.R. (1983). An adenosine agonist inhibits and a cyclic AMP analogue enhances the release of glutamate but not GABA from slices of rat dentate gyrus. Neurosci. Lett., 43, 49–54.PubMedCrossRefGoogle Scholar
  24. Dunwiddle, T.V. and Worth, T. (1982). Sedative and anticonvulsant effects of adenosine analogs in mouse and rat. J. Pharmacol, exp. Therap., 220, 70–76.Google Scholar
  25. Evans, R.H., Francis, A.A., Jones, A.W., Smith, D.A.S., Watkins, J.C. (1982). The effects of a series of?-phosphonic a-carboxylic amino acids on electrically evoked and excitant amino acid-induced responses in isolated spinal cord preparations. Brit. J. Pharmacol., 75, 65–75.CrossRefGoogle Scholar
  26. Freed, W.J. (1985). Selective inhibition of homocysteine-induced seizures by glutamic acid diethyl ester and other glutamate esters. Epilepsia, 26, 10–36.CrossRefGoogle Scholar
  27. Freed, W.J. and Michaelis, E.K. (1978). Glutamic acid and ethanol dependence. Pharmacol. Biochem. Behav., 8, 509–514.PubMedCrossRefGoogle Scholar
  28. Goodman, R.R., Kuhar, M.J., Hester, L. and Snyder, S.H. (1983). Adenosine receptors: Autoradiographic evidence for their location on axon terminals of excitatory neurons. Science, 220, 967–969.PubMedCrossRefGoogle Scholar
  29. Harris, E.W., Ganong, A.H. and Cotman, C.W. (1984). Long-term potentiation in the hippocampus involves activation of N-methyl-D-aspartate receptors. Brain Res., 323, 132–137.PubMedCrossRefGoogle Scholar
  30. Herman, Z.S. (1975). Behavioural changes induced in conscious mice by intracerebroventricular injection of catecholamines, acetylcholine and 5-hydroxytryptamine. Br. J. Pharmacol., 55, 351–358.PubMedPubMedCentralCrossRefGoogle Scholar
  31. Herrling, P.L., Morris, R. and Salt, T.E. (1983). Effects of excitatory amino acids and their antagonists on membrane and action potentials of cat caudate neurones. J. Physiol. 339, 207.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Holtman, J.R. and Richter, J.A. (1983). Comparison of the effects of a convulsant barbiturate on the release of endogenous and radio-labelled amino acids from slices of mouse hippocampus. J. Neurochem. 41, 723–728.PubMedCrossRefGoogle Scholar
  33. Horton, R., anlezark, G. and Meldrum, B. (1980). Noradrenergic influences on sound-induced seizures. J. Pharmacol. Exp. Ther., 214, 437–442.PubMedGoogle Scholar
  34. Jones, A.W., Smith, D.A.S. and Watkins, J.C. (1984a). Structure-activity relations of dipeptide antagonists of excitatory amino acids. Neuroscience, 13, 573–581.PubMedCrossRefGoogle Scholar
  35. Jones, A.W., Croucher, M.J., Meldrum, B.S. and Watkins, J.C. (1984b). Suppression of audiogenic seizures in DBA/2 mice by two new dipeptide NMDA receptor antagonists. Neurosci. Lett., 45, 157–161.PubMedCrossRefGoogle Scholar
  36. Kerwin, R.W. and Meldrum, B.S. (1983). Effect on cerebral 3H-D-aspartate release of 3-mercaptopropionic acid and methyl 5,7-dimethoxy-4-ethyl-ß-carboline-3-carboxylate. Eur. J. Pharmacol., 89, 265.PubMedCrossRefGoogle Scholar
  37. Lee, K.S., Schubert, P. and Heinemann, U. (1984). The anticonvulsive action of adenosine: a post-synaptic, dendritic action by a possible endogenous anticonvulsant. Brain Res. 321, 160–164.PubMedCrossRefGoogle Scholar
  38. MacDonald, J.F., Porietis, A.V. and Wojtowicz, J.M. (1982). Aspartic acid induces a region of negative slope conductance in the current-voltage relationship of cultured spinal cord neurons. Brain Res., 237, 248–253.PubMedCrossRefGoogle Scholar
  39. MacDonald, R.L. (1983). Mechanisms of anticonvulsant drug action. In Recent Advances in Epilepsy. (eds. T.A. Pedley and B.S. Meldrum). Churchill Livingstone Edinburgh.Google Scholar
  40. McBean, G.J. and Roberts, P.J. (1981). Glutamate-preferring receptors regulate the release of D-3H aspartate from rat hippocampal slices. Nature 291, 593–594.PubMedCrossRefGoogle Scholar
  41. McLennan, H. (1984). Receptors for the excitatory amino acids in the mammalian central nervous system. Prog. Neurobiol., 20, 251–271.CrossRefGoogle Scholar
  42. Mayer, M.L. and Westbrook, G.L. (1984). Mixedagonist action of excitatory amino acids on mouse spinal cord neurones under voltage clamp. J. Physiol. (Lond.), 354, 29–53.CrossRefGoogle Scholar
  43. Meldrum, B.S. (1978). Photosensitive epilepsy in Papio papio as a model for drug studies. In Contemporary Clinical Neurophysiology, Suppl. 34: Electroencephalography Clinical Neurophysiology, (eds. E.A. Cobb and H. van Duijn). Elsevier, Amsterdam.Google Scholar
  44. Meldrum, B.S. (1983). Pharmacological considerations in the search for new anticonvulsant drugs. In Recent Advances in Epilepsy. (eds. T.A. Pedley and B.S. Meldrum). Churchill Livingstone, London.Google Scholar
  45. Meldrum, B. and Braestrup, C. (1984). GABA and the Anticonvulsant Action of Benzodiazepines and Related Drugs. In Actions and Interactions of GABA and Benzodiazepines. (eds. N.G. Bowery). Raven Press, New York.Google Scholar
  46. Meldrum, B.S., Croucher, M.J., Badman, G. and Collins, J.F. (1983a). Antiepileptic action of excitatory amino acid antagonists in the photosensitive baboon, Papio papio. Neurosci. Lett., 39, 101–104.PubMedCrossRefGoogle Scholar
  47. Meldrum, B.S., Croucher, M.J., Czuczwar, S.J., Collins, J.F., Curry, K., Joseph, M. and Stone, T.W. (1983b). A comparison of the anticonvulsant potency of (±)2-amino-5-phosphonopentanoic acid and (±)2-amino-7-phosphonoheptanoic acid. Neuroscience 9, 925–930.PubMedCrossRefGoogle Scholar
  48. Meldrum, B., Wardley-Smith, B., Halsey, M., Rostain, J.C. (1983c). Phosphonoheptanoic acid protects against the high pressure neurological syndrome. Eur. J. Pharmacol., 87, 501–502.PubMedCrossRefGoogle Scholar
  49. Minchin, M.C.W. (1981). The effect of anaesthetics on the uptake and release of?-aminobutyrate and D-aspartate in rat brain slices. Brit. J. Pharmac, 73, 681–689.CrossRefGoogle Scholar
  50. Nahorski, S.R. (1972). Biochemical effects of the anticonvulsants trimethadione, ethosuximide and chlordiazepoxide in rat brain. J. Neurochem. 19, 1937–1946.PubMedCrossRefGoogle Scholar
  51. Nowak, L., Bregestovski, P., Ascher, P., Herbet, A. and Prochiantz, A. (1984). Magnesium gates glutamateactivated channels in mouse central neurones. Nature (Lond.), 307, 462–465.CrossRefGoogle Scholar
  52. Peet, M.J., Leah, J.D. and Curtis, D.R. (1983). Antagonists of synaptic and amino acid excitation of neurons in the cat spinal cord. Brain Res., 266, 83–95.PubMedCrossRefGoogle Scholar
  53. Peterson, D.W., Collins, J.F. and Bradford, H.F. (1983). The kindled amygdala model of epilepsy: anticonvulsant action of amino acid antagonists. Brain Res., 275, 169–172.PubMedCrossRefGoogle Scholar
  54. Potashner, S.J. (1979). Baclofen: Effects on amino acid release in slices of guinea pig cerebral cortex. J. Neurochem., 32, 103.PubMedCrossRefGoogle Scholar
  55. Reubi, J.C, Toggenburger, G. and Guenod, M. (1980). Asparagine as precursor for transmitter aspartate in corticostriatal fibres. J. Neurochem., 35., 1015.PubMedCrossRefGoogle Scholar
  56. Schechter, P.J., Tranier, Y., Grove, J. (1978). Effect of n-dipro-pylacetate on amino acid concentrations in mouse brain: correlations with anticonvulsant activity. J. Neurochem., 31, 1325–1327.PubMedCrossRefGoogle Scholar
  57. Schwartzkroin, P.A., Wyler, A.R. (1980). Mechanisms underlying epileptiform burst discharge. Ann. Neurol. 7, 95.PubMedCrossRefGoogle Scholar
  58. Skerritt, J.H., Johnston, G.A.R. (1984). Modulation of excitant amino acid release by convulsant and anticonvulsant drugs. In Neurotransmitters, Seizures and Epilepsy II. (eds. R.G. Fariello). pp.215–226, Raven Press, New York.Google Scholar
  59. Skerritt, J.H., Willow, M. and Johnston, G.A.R. (1983). Contrasting effects of a convulsant (CHEB) and an anticonvulsant barbiturate (Phenobarbitone) on amino acid release from rat brain slices. Brain Res., 258, 271–276.PubMedCrossRefGoogle Scholar
  60. Turski, L., Collins, J.F. and Meldrum, B.S. (1985). Is 3-kainic acid an N-methyl-Daspartate antagonist? Brain Res., 336, 162–166.PubMedCrossRefGoogle Scholar
  61. Wardley-Smith, B. & Meldrum, B.S. (1984). Effect of excitatory amino acid antagonists on the high pressure neurological syndrome in rats. Eur. J. Pharmacol., 105, 351–354.PubMedCrossRefGoogle Scholar

Copyright information

© The Editors and the Contributors 1986

Authors and Affiliations

  • B. S. Meldrum
  • A. G. Chapman
  • L. M. Mello
  • M. H. Millan
  • S. Patel
  • L. Turski

There are no affiliations available

Personalised recommendations