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. 1989;27(Suppl 1):3S–11S. doi: 10.1111/j.1365-2125.1989.tb03454.x

GABAergic mechanisms in the pathogenesis and treatment of epilepsy

B S Meldrum
PMCID: PMC1379672  PMID: 2667605

Abstract

1 Evidence relating to the role of GABA in the pathogenesis of epilepsy is reviewed.

2 Impaired GABAergic function appears to contribute to seizure susceptibility in a variety of genetically-determined syndromes in animals, e.g. genetically epilepsy prone rats showing sound-induced seizures, gerbils with genetically determined epilepsy, and baboons, Papio papio, with photosensitive epilepsy.

3 In epilepsy secondary to a cerebral insult there is some morphological and biochemical evidence for impaired GABAergic function in experimental situations, but little definitive evidence in man.

4 Pharmacological approaches to enhancing GABAergic inhibition include the use of GABA agonists (or prodrugs), GABA-transaminase inhibition, GABA uptake inhibition, and action at the GABA/benzodiazepine allosteric site.

5 Experimental data suggest that the best prospect for potent anticonvulsant action with fewest side effects (myoclonus, sedation, ataxia) is at present offered by GABA-transaminase inhibitors or novel agents acting on the benzodiazepine receptor site.

Keywords: GABA, epilepsy

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Selected References

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  1. Abdul-Ghani A. S., Coutinho-Netto J., Bradford H. F. The action of gamma-vinyl-GABA and gamma-acetylenic-GABA on the resting and stimulated release of GABA in vivo. Brain Res. 1980 Jun 9;191(2):471–481. doi: 10.1016/0006-8993(80)91295-0. [DOI] [PubMed] [Google Scholar]
  2. Anderson W. R., Simpkins J. W., Woodard P. A., Winwood D., Stern W. C., Bodor N. Anxiolytic activity of a brain delivery system for GABA. Psychopharmacology (Berl) 1987;92(2):157–163. doi: 10.1007/BF00177908. [DOI] [PubMed] [Google Scholar]
  3. Anlezark G., Horton R. W., Meldrium B. S., Sawaya C. B. Anticonvulsant action of ethanolamine-O-sulphate and di-n-propylacetate and the metabolism of gamma-aminobutyric acid (GABA) in mice with audiogenic seizures. Biochem Pharmacol. 1976 Feb 15;25(4):413–417. doi: 10.1016/0006-2952(76)90343-9. [DOI] [PubMed] [Google Scholar]
  4. Bowery N. G., Hill D. R., Hudson A. L., Doble A., Middlemiss D. N., Shaw J., Turnbull M. (-)Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature. 1980 Jan 3;283(5742):92–94. doi: 10.1038/283092a0. [DOI] [PubMed] [Google Scholar]
  5. Bowery N. G., Hudson A. L., Price G. W. GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience. 1987 Feb;20(2):365–383. doi: 10.1016/0306-4522(87)90098-4. [DOI] [PubMed] [Google Scholar]
  6. Brailowsky S., Menini C., Silva-Barrat C., Naquet R. Epileptogenic gamma-aminobutyric acid-withdrawal syndrome after chronic, intracortical infusion in baboons. Neurosci Lett. 1987 Feb 10;74(1):75–80. doi: 10.1016/0304-3940(87)90054-1. [DOI] [PubMed] [Google Scholar]
  7. Chapman A., Keane P. E., Meldrum B. S., Simiand J., Vernieres J. C. Mechanism of anticonvulsant action of valproate. Prog Neurobiol. 1982;19(4):315–359. doi: 10.1016/0301-0082(82)90010-7. [DOI] [PubMed] [Google Scholar]
  8. Chisholm J., Kellogg C., Franck J. E. Developmental hyperthermic seizures alter adult hippocampal benzodiazepine binding and morphology. Epilepsia. 1985 Mar-Apr;26(2):151–157. doi: 10.1111/j.1528-1157.1985.tb05399.x. [DOI] [PubMed] [Google Scholar]
  9. Curtis D. R., Lodge D., Johnston G. A., Brand S. J. Central actions of benzodiazepines. Brain Res. 1976 Dec 17;118(2):344–347. doi: 10.1016/0006-8993(76)90723-x. [DOI] [PubMed] [Google Scholar]
  10. Danzin C., Claverie N., Jung M. J. Stereochemistry of the inactivation of 4-aminobutyrate: 2-oxoglutarate aminotransferase and L-glutamate 1-carboxylase by 4-aminohex-5-ynoic acid enantiomers. Biochem Pharmacol. 1984 Jun 1;33(11):1741–1746. doi: 10.1016/0006-2952(84)90343-5. [DOI] [PubMed] [Google Scholar]
  11. De Deyn P. P., Macdonald R. L. CGS 9896 and ZK 91296, but not CGS 8216 and RO 15-1788, are pure benzodiazepine receptor antagonists on mouse neurons in culture. J Pharmacol Exp Ther. 1987 Jul;242(1):48–55. [PubMed] [Google Scholar]
  12. Falch E., Meldrum B. S., Krogsgaard-Larsen P. GABA uptake inhibitors. Synthesis and effects on audiogenic seizures of ester prodrugs of nipecotic acid, guvacine and cis-4-hydroxynipecotic acid. Drug Des Deliv. 1987 Sep;2(1):9–21. [PubMed] [Google Scholar]
  13. Ferrero P., Costa E., Conti-Tronconi B., Guidotti A. A diazepam binding inhibitor (DBI)-like neuropeptide is detected in human brain. Brain Res. 1986 Dec 3;399(1):136–142. doi: 10.1016/0006-8993(86)90607-4. [DOI] [PubMed] [Google Scholar]
  14. Fowler L. J., John R. A. Active-site-directed irreversible inhibition of rat brain 4-aminobutyrate aminotransferase by ethanolamine O-sulphate in vitro and in vivo. Biochem J. 1972 Nov;130(2):569–573. doi: 10.1042/bj1300569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Frey H. H., Löscher W. Cetyl GABA: effect on convulsant thresholds in mice and acute toxicity. Neuropharmacology. 1980 Feb;19(2):217–220. doi: 10.1016/0028-3908(80)90141-0. [DOI] [PubMed] [Google Scholar]
  16. Fromm G. H., Terrence C. F., Chattha A. S. Comparison of progabide with other antiepileptic and GABAergic drugs. Epilepsia. 1985 Nov-Dec;26(6):672–681. doi: 10.1111/j.1528-1157.1985.tb05710.x. [DOI] [PubMed] [Google Scholar]
  17. Galzigna L., Garbin L., Bianchi M., Marzotto A. Properties of two derivatives of gamma-aminobutyric acid (GABA) capable of abolishing Cardiazol- and bicuculline-induced convulsions in the rat. Arch Int Pharmacodyn Ther. 1978 Sep;235(1):73–85. [PubMed] [Google Scholar]
  18. Guidotti A., Forchetti C. M., Corda M. G., Konkel D., Bennett C. D., Costa E. Isolation, characterization, and purification to homogeneity of an endogenous polypeptide with agonistic action on benzodiazepine receptors. Proc Natl Acad Sci U S A. 1983 Jun;80(11):3531–3535. doi: 10.1073/pnas.80.11.3531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Horton R. W., Prestwich S. A., Meldrum B. S. gamma-Aminobutyric acid and benzodiazepine binding sites in audiogenic seizure-susceptible mice. J Neurochem. 1982 Sep;39(3):864–870. doi: 10.1111/j.1471-4159.1982.tb07972.x. [DOI] [PubMed] [Google Scholar]
  20. Houser C. R., Hendry S. H., Jones E. G., Vaughn J. E. Morphological diversity of immunocytochemically identified GABA neurons in the monkey sensory-motor cortex. J Neurocytol. 1983 Aug;12(4):617–638. doi: 10.1007/BF01181527. [DOI] [PubMed] [Google Scholar]
  21. Krogsgaard-Larsen P. Inhibitors of the GABA uptake systems. Mol Cell Biochem. 1980 Jun 18;31(2):105–121. doi: 10.1007/BF00240816. [DOI] [PubMed] [Google Scholar]
  22. Kuriyama K., Roberts E., Rubinstein M. K. Elevation of gamma-aminobutyric acid in brain with amino-oxyacetic acid and susceptibility to convulsive seizures in mice: a quantitative re-evaluation. Biochem Pharmacol. 1966 Mar;15(3):221–236. doi: 10.1016/0006-2952(66)90293-0. [DOI] [PubMed] [Google Scholar]
  23. Lloyd K. G., Arbilla S., Beaumont K., Briley M., De Montis G., Scatton B., Langer S. Z., Bartholini G. gamma-Aminobutyric acid (GABA) receptor stimulation. II. Specificity of progabide (SL 76002) and SL 75102 for the GABA receptor. J Pharmacol Exp Ther. 1982 Mar;220(3):672–677. [PubMed] [Google Scholar]
  24. Loeb C., Besio G., Mainardi P., Scotto P., Benassi E., Bo G. P. Liposome-entrapped gamma-aminobutyric acid inhibits isoniazid-induced epileptogenic activity in rats. Epilepsia. 1986 Mar-Apr;27(2):98–102. doi: 10.1111/j.1528-1157.1986.tb03509.x. [DOI] [PubMed] [Google Scholar]
  25. Löscher W. Anticonvulsant action in the epileptic gerbil of novel inhibitors of GABA uptake. Eur J Pharmacol. 1985 Mar 26;110(1):103–108. doi: 10.1016/0014-2999(85)90034-2. [DOI] [PubMed] [Google Scholar]
  26. Löscher W. Effect of inhibitors of GABA aminotransferase on the metabolism of GABA in brain tissue and synaptosomal fractions. J Neurochem. 1981 Apr;36(4):1521–1527. doi: 10.1111/j.1471-4159.1981.tb00595.x. [DOI] [PubMed] [Google Scholar]
  27. Löscher W., Frey H. H., Reiche R., Schultz D. High anticonvulsant potency of gamma-aminobutyric acid (GABA)mimetic drugs in gerbils with genetically determined epilepsy. J Pharmacol Exp Ther. 1983 Sep;226(3):839–844. [PubMed] [Google Scholar]
  28. Löscher W., Rating D., Siemes H. GABA in cerebrospinal fluid of children with febrile convulsions. Epilepsia. 1981 Dec;22(6):697–702. doi: 10.1111/j.1528-1157.1981.tb04143.x. [DOI] [PubMed] [Google Scholar]
  29. Löscher W., Siemes H. Cerebrospinal fluid gamma-aminobutyric acid levels in children with different types of epilepsy: effect of anticonvulsant treatment. Epilepsia. 1985 Jul-Aug;26(4):314–319. doi: 10.1111/j.1528-1157.1985.tb05656.x. [DOI] [PubMed] [Google Scholar]
  30. Manyam N. V., Katz L., Hare T. A., Gerber J. C., 3rd, Grossman M. H. Levels of gamma-aminobutyric acid in cerebrospinal fluid in various neurologic disorders. Arch Neurol. 1980 Jun;37(6):352–355. doi: 10.1001/archneur.1980.00500550054006. [DOI] [PubMed] [Google Scholar]
  31. Marquardt H., Todaro G. J., Shoyab M. Complete amino acid sequences of bovine and human endozepines. Homology with rat diazepam binding inhibitor. J Biol Chem. 1986 Jul 25;261(21):9727–9731. [PubMed] [Google Scholar]
  32. Meldrum B. S., BChir, Horton R. W., Toseland P. A. A primate model for testing anticonvulsant drugs. Arch Neurol. 1975 May;32(5):289–294. doi: 10.1001/archneur.1975.00490470033003. [DOI] [PubMed] [Google Scholar]
  33. Meldrum B. S., Chapman A. G. Benzodiazepine receptors and their relationship to the treatment of epilepsy. Epilepsia. 1986;27 (Suppl 1):S3–13. doi: 10.1111/j.1528-1157.1986.tb05731.x. [DOI] [PubMed] [Google Scholar]
  34. Meldrum B. S. Epilepsy and gamma-aminobutyric acid-mediated inhibition. Int Rev Neurobiol. 1975;17:1–36. doi: 10.1016/s0074-7742(08)60205-6. [DOI] [PubMed] [Google Scholar]
  35. Meldrum B. S., Evans M. C., Braestrup C. Anticonvulsant action in the photosensitive baboon, Papio papio, of a novel beta-carboline derivative, ZK 91296. Eur J Pharmacol. 1983 Jul 22;91(2-3):255–259. doi: 10.1016/0014-2999(83)90474-0. [DOI] [PubMed] [Google Scholar]
  36. Meldrum B. S. Gamma-aminobutyric acid and the search for new anticonvulsant drugs. Lancet. 1978 Aug 5;2(8084):304–306. doi: 10.1016/s0140-6736(78)91703-8. [DOI] [PubMed] [Google Scholar]
  37. Meldrum B. S., Murugaiah K. Anticonvulsant action in mice with sound-induced seizures of the optical isomers of gamma-vinyl GABA. Eur J Pharmacol. 1983 Apr 22;89(1-2):149–152. doi: 10.1016/0014-2999(83)90620-9. [DOI] [PubMed] [Google Scholar]
  38. Meldrum B., Horton R. Blockade of epileptic responses in the photosensitive baboon, Papio papio, by two irreversible inhibitors of GABA-transaminase, gamma-acetylenic GABA (4-amino-hex-5-ynoic acid) and gamma-vinyl GABA (4-amino-hex-5-enoic acid). Psychopharmacology (Berl) 1978 Sep 15;59(1):47–50. doi: 10.1007/BF00428029. [DOI] [PubMed] [Google Scholar]
  39. Meldrum B., Horton R. Effects of the bicyclic GABA agonist, THIP, on myoclonic and seizure responses in mice and baboons with reflex epilepsy. Eur J Pharmacol. 1980 Feb 8;61(3):231–237. doi: 10.1016/0014-2999(80)90125-9. [DOI] [PubMed] [Google Scholar]
  40. Möhler H., Okada T. Benzodiazepine receptor: demonstration in the central nervous system. Science. 1977 Nov 25;198(4319):849–851. doi: 10.1126/science.918669. [DOI] [PubMed] [Google Scholar]
  41. Newberry N. R., Nicoll R. A. Direct hyperpolarizing action of baclofen on hippocampal pyramidal cells. 1984 Mar 29-Apr 4Nature. 308(5958):450–452. doi: 10.1038/308450a0. [DOI] [PubMed] [Google Scholar]
  42. Olsen R. W. Drug interactions at the GABA receptor-ionophore complex. Annu Rev Pharmacol Toxicol. 1982;22:245–277. doi: 10.1146/annurev.pa.22.040182.001333. [DOI] [PubMed] [Google Scholar]
  43. Olsen R. W., Wamsley J. K., McCabe R. T., Lee R. J., Lomax P. Benzodiazepine/gamma-aminobutyric acid receptor deficit in the midbrain of the seizure-susceptible gerbil. Proc Natl Acad Sci U S A. 1985 Oct;82(19):6701–6705. doi: 10.1073/pnas.82.19.6701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Palfreyman M. G., Schechter P. J., Buckett W. R., Tell G. P., Koch-Weser J. The pharmacology of GABA-transaminase inhibitors. Biochem Pharmacol. 1981 Apr 15;30(8):817–824. doi: 10.1016/s0006-2952(81)80001-9. [DOI] [PubMed] [Google Scholar]
  45. Pedley T. A., Horton R. W., Meldrum B. S. Electroencephalographic and behavioral effects of a GABA agonist (muscimol) on photosensitive epilepsy in the baboon, papio papio. Epilepsia. 1979 Aug;20(4):409–416. doi: 10.1111/j.1528-1157.1979.tb04821.x. [DOI] [PubMed] [Google Scholar]
  46. Peterson G. M., Ribak C. E., Oertel W. H. A regional increase in the number of hippocampal GABAergic neurons and terminals in the seizure-sensitive gerbil. Brain Res. 1985 Aug 12;340(2):384–389. doi: 10.1016/0006-8993(85)90937-0. [DOI] [PubMed] [Google Scholar]
  47. Ribak C. E., Bradburne R. M., Harris A. B. A preferential loss of GABAergic, symmetric synapses in epileptic foci: a quantitative ultrastructural analysis of monkey neocortex. J Neurosci. 1982 Dec;2(12):1725–1735. doi: 10.1523/JNEUROSCI.02-12-01725.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Ribak C. E., Harris A. B., Vaughn J. E., Roberts E. Inhibitory, GABAergic nerve terminals decrease at sites of focal epilepsy. Science. 1979 Jul 13;205(4402):211–214. doi: 10.1126/science.109922. [DOI] [PubMed] [Google Scholar]
  49. Roberts R. C., Ribak C. E., Oertel W. H. Increased numbers of GABAergic neurons occur in the inferior colliculus of an audiogenic model of genetic epilepsy. Brain Res. 1985 Dec 30;361(1-2):324–338. doi: 10.1016/0006-8993(85)91303-4. [DOI] [PubMed] [Google Scholar]
  50. SCOTTO P., MONACO P., SCARDI V., BONAVITA V. NEUROCHEMICAL STUDIES WITH L-CYCLOSERINE, A CENTRAL DEPRESSANT AGENT. J Neurochem. 1963 Dec;10:831–839. doi: 10.1111/j.1471-4159.1963.tb11908.x. [DOI] [PubMed] [Google Scholar]
  51. Schofield P. R., Darlison M. G., Fujita N., Burt D. R., Stephenson F. A., Rodriguez H., Rhee L. M., Ramachandran J., Reale V., Glencorse T. A. Sequence and functional expression of the GABA A receptor shows a ligand-gated receptor super-family. Nature. 1987 Jul 16;328(6127):221–227. doi: 10.1038/328221a0. [DOI] [PubMed] [Google Scholar]
  52. Sloper J. J., Johnson P., Powell T. P. Selective degeneration of interneurons in the motor cortex of infant monkeys following controlled hypoxia: a possible cause of epilepsy. Brain Res. 1980 Sep 29;198(1):204–209. doi: 10.1016/0006-8993(80)90356-x. [DOI] [PubMed] [Google Scholar]
  53. Sloviter R. S. Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science. 1987 Jan 2;235(4784):73–76. doi: 10.1126/science.2879352. [DOI] [PubMed] [Google Scholar]
  54. Somogyi P., Freund T. F., Hodgson A. J., Somogyi J., Beroukas D., Chubb I. W. Identified axo-axonic cells are immunoreactive for GABA in the hippocampus and visual cortex of the cat. Brain Res. 1985 Apr 15;332(1):143–149. doi: 10.1016/0006-8993(85)90397-x. [DOI] [PubMed] [Google Scholar]
  55. Somogyi P., Soltész I. Immunogold demonstration of GABA in synaptic terminals of intracellularly recorded, horseradish peroxidase-filled basket cells and clutch cells in the cat's visual cortex. Neuroscience. 1986 Dec;19(4):1051–1065. doi: 10.1016/0306-4522(86)90122-3. [DOI] [PubMed] [Google Scholar]
  56. Study R. E., Barker J. L. Diazepam and (--)-pentobarbital: fluctuation analysis reveals different mechanisms for potentiation of gamma-aminobutyric acid responses in cultured central neurons. Proc Natl Acad Sci U S A. 1981 Nov;78(11):7180–7184. doi: 10.1073/pnas.78.11.7180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Vergnes M., Marescaux C., Micheletti G., Depaulis A., Rumbach L., Warter J. M. Enhancement of spike and wave discharges by GABAmimetic drugs in rats with spontaneous petit-mal-like epilepsy. Neurosci Lett. 1984 Jan 27;44(1):91–94. doi: 10.1016/0304-3940(84)90226-x. [DOI] [PubMed] [Google Scholar]
  58. Wood J. H., Hare T. A., Glaeser B. S., Ballenger J. C., Post R. M. Low cerebrospinal fluid gamma-aminobutyric acid content in seizure patients. Neurology. 1979 Sep;29(9 Pt 1):1203–1208. doi: 10.1212/wnl.29.9_part_1.1203. [DOI] [PubMed] [Google Scholar]
  59. Worms P., Depoortere H., Durand A., Morselli P. L., Lloyd K. G., Bartholini G. gamma-Aminobutyric acid (GABA) receptor stimulation. I. Neuropharmacological profiles of progabide (SL 76002) and SL 75102, with emphasis on their anticonvulsant spectra. J Pharmacol Exp Ther. 1982 Mar;220(3):660–671. [PubMed] [Google Scholar]
  60. Yunger L. M., Fowler P. J., Zarevics P., Setler P. E. Novel inhibitors of gamma-aminobutyric acid (GABA) uptake: anticonvulsant actions in rats and mice. J Pharmacol Exp Ther. 1984 Jan;228(1):109–115. [PubMed] [Google Scholar]
  61. Zorn S. H., Duman R. S., Giachetti A., Micheletti R., Giraldo E., Krogsgaard-Larsen P., Enna S. J. (R)-nipecotic acid ethyl ester: a direct-acting cholinergic agonist that displays greater efficacy at M2 than at M1 muscarinic receptors. J Pharmacol Exp Ther. 1987 Jul;242(1):173–178. [PubMed] [Google Scholar]

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