JLE

Epileptic Disorders

MENU

Update on the mechanisms of action of antiepileptic drugs Volume 3, issue 4, December 2001

1. Hauptmann A. Luminal bei epilepsie. Münch Med Wochenschr 1912; 59: 1907-9.

2. Brodie MJ, Dichter MA. Antiepileptic drugs. N Engl J Med 1996; 334: 168-75.

3. Brodie MJ, Dichter MA. Established antiepileptic drugs. Seizure 1997; 6: 159-74.

4. Leach JP, Brodie MJ. New antiepileptic drugs - an explosion of activity. Seizure 1995; 4: 5-17.

5. Dichter MA, Brodie MJ. New antiepileptic drugs. N Engl J Med 1996; 334: 1583-90.

6. Brodie MJ, French JA. Management of epilepsy in adolescents and adults. Lancet 2000; 356: 323-9.

7. Brodie MJ, Kwan P. The "star" systems: overview and use in determining drug choice for patients with epilepsy. CNS Drugs 2001; 18: 1-12.

8. Rogawski MA, Porter RJ. Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev 1990; 42: 223-86.

9. Macdonald RL, Rogers CJ, Twyman RE. Barbiturate regulation of kinetic properties of the GABAA receptor channel of mouse spinal neurones in culture. J Physiol 1989; 417: 483-500.

10. Twyman RE, Rogers CJ, Macdonald RL. Differential regulation of gamma-aminobutyric acid receptor channels by diazepam and phenobarbital. Ann Neurol 1989; 25: 213-20.

11. Rho JM, Donevan SD, Rogawski MA. Direct activation of GABAA receptors by barbiturates in cultured rat hippocampal neurons. J Physiol 1996; 497: 509-22.

12. White HS. Comparative anticonvulsant and mechanistic profile of established and newer antiepileptic drugs. Epilepsia 1999; 40 (suppl 5): S2-10.

13. Davies JA. Mechanisms of action of antiepileptic drugs. Seizure 1995; 4: 267-72.

14. Tunnicliff G. Basis of the antiseizure action of phenytoin. Gen Pharmacol 1996; 27: 1091-7.

15. McLean MJ, Macdonald RL. Multiple actions of phenytoin on mouse spinal cord neurons in cell culture. J Pharmacol Exp Ther 1983; 227: 779-89.

16. Schwartz JR, Grigat G. Phenytoin and carbamazepine: potential- and frequency-dependent block of Na+ currents in mammalian myelinated nerve fibers. Epilepsia 1989; 30: 286-94.

17. Schumacher TB, Beck H, Steinhauser C, et al. Effects of phenytoin, carbamazepine, and gabapentin on calcium channels in hippocampal granule cells from patients with temporal lobe epilepsy. Epilepsia 1998; 39: 355-63.

18. Rowley HL, Marsden CA, Martin KF. Differential effects of phenytoin and sodium valproate on seizure-induced changes in gamma-aminobutyric acid and glutamate release in vivo. Eur J Pharmacol 1995; 294: 541-6.

19. Granger P, Biton B, Faure C, et al. Modulation of the gamma-aminobutyric acid type A receptor by the antiepileptic drugs carbamazepine and phenytoin. Mol Pharmacol 1995; 47: 1189-96.

20. Courtney KR, Etter EF. Modulated anticonvulsant block of sodium channels in nerve and muscle. Eur J Pharmacol 1983; 88: 1-9.

21. Kuo CC, Chen RS, Lu L, et al. Carbamazepine inhibition of neuronal Na+ currents: quantitative distinction from phenytoin and possible therapeutic implications. Mol Pharmacol 1997; 51: 1077-83.

22. Hough CJ, Irwin RP, Gao XM, et al. Carbamazepine inhibition of N-methyl-D-aspartate-evoked calcium influx in
rat cerebellar granule cells. J Pharmacol Exp Ther 1996; 276: 143-9.

23. Waldmeier PC, Baumann PA, Wicki P, et al. Similar potency of carbamazepine, oxcarbazepine, and lamotrigine in inhibiting the release of glutamate and other neurotransmitters. Neurology 1995; 45: 1907-13.

24. Dailey JW, Reith ME, Yan QS, et al. Anticonvulsant doses of carbamazepine increase hippocampal extracellular serotonin in genetically epilepsy-prone rats: dose response relationships. Neurosci Lett 1997; 227: 13-6.

25. Dailey JW, Reith ME, Yan QS, et al. Carbamazepine increases extracellular serotonin concentration: lack of antagonism by tetrodotoxin or zero Ca2+. Eur J Pharmacol 1997; 328: 153-62.

26. Marangos PJ, Post RM, Patel J, et al. Specific and potent interactions of carbamazepine with brain adenosine receptors. Eur J Pharmacol 1983; 93: 175-82.

27. Bourgeois BFD. Primidone. Biotransformation and mechanisms of action. In: Levy R, Mattson RH, Meldrum BS, Penry JK, Dreifuss FE. Antiepileptic Drugs, 3rd edition. New York: Raven Press, 1989: 401-12.

28. Bourgeois BFD, Dodson WE, Ferrendelli JA. Primidone, phenobarbital and PEMA: I. Seizure protection, neurotoxicity and therapeutic index of individual compounds in mice. Neurology 1983; 33: 283-90.

29. Mattson RH, Cramer JA, Collins JF, et al. Comparison of carbamazepine, phenobarbital, phenytoin and primidone in partial and secondary generalised tonic-clonic seizures. N Engl J Med 1985; 313: 145-51.

30. McLean MJ, Macdonald L. Sodium valproate, but not ethosuximide, produces use- and voltage-dependent limitation of high frequency repetitive firing of action potentials of mouse central neurons in cell culture. J Pharmacol Exp Ther 1986; 237: 1001-11.

31. van Dongen AMJ, van Erp MG, Voskuyl RA. Valproate reduces excitability by blockage of sodium and potassium conductance. Epilepsia 1986; 27: 177-82.

32. Zona C, Avoli M. Effects induced by the antiepileptic drug valproic acid upon the ionic currents recorded in rat neocortical neurons in cell culture. Exp Brain Res 1990; 81: 313-7.

33. Albus H, Williamson R. Electrophysiologic analysis of the actions of valproate on pyramidal neurons in the rat hippocampal slices. Epilepsia 1998; 39: 124-39.

34. Kelly KM, Gross RA, Macdonald RL. Valproic acid selectively reduces the low-threshold (T) calcium current in rat nodose neurons. Neurosci Lett 1990; 116: 233-8.

35. Coulter DA, Huguenard JR, Prince DA. Characterization of ethosuximide reduction of low-threshold calcium currents in thalamic neurons. Ann Neurol 1989; 25: 582-93.

36. Schechter PJ, Tranier Y, Grove J. Effect of n-dipropylacetate on amino acid concentrations in mouse brain: correlation with anticonvulsant activity. J Neurochem 1978; 31: 1325-7.

37. Chapman AG, Meldrum BS, Mendes E. Acute anticonvulsant activity of structural analogues of valproic acid and changes in brain GABA and aspartate content. Life Sci 1983; 32: 2023-31.

38. Chapman AG, Croucher MJ, Meldrum BS. Anticonvulsant activity of intracerebroventricularly administered valproate and valproate analogues. A dose-dependent correlation with changes in brain asparate and GABA levels in DBA/2 mice. Biochem Pharmacol 1984; 33: 1459-63.

39. Löscher W. Valproate: a reappraisal of its pharmacodynamic properties and mechanisms of action. Prog Neurobiol 1999; 58: 31-59.

40. Sills GJ, Leach JP, Butler E, et al. Antiepileptic drug action in primary cultures of rat cortical astrocytes. Epilepsia 1996; 37 (suppl 4): 116.

41. Coulter DA, Huguenard JR, Prince DA. Specific petit mal anticonvulsants reduce calcium currents in thalamic neurons. Neurosci Lett 1989; 98: 74-8.

42. Coulter DA, Huguenard JR, Prince DA. Calcium currents in rat thalamocortical relay neurones: kinetic properties of the transient low-threshold current. J Physiol 1989; 414: 587-604.

43. Macdonald RL, Kelly KM. Antiepileptic drug mechanisms of action. Epilepsia 1995; 36 (suppl 2): S2-12.

44. Study RE, Barker JL. Diazepam and (-)-pentobarbital: fluctuation analysis reveals different mechanisms for potentiation of gamma-aminobutyric acid responses in cultured central neurons. Proc Natl Acad Sci USA 1981; 78: 7180-4.

45. Czuczwar SJ, Patsalos PN. The new generation of GABA enhancers. Potential in the treatment of epilepsy. CNS Drugs 2001; 15: 339-50.

46. Coulter DA. Antiepileptic drug cellular mechanisms of action: where does lamotrigine fit in? J Child Neurol 1997; 12 (suppl 1): S2-9.

47. Koch A, Woodbury DM. Carbonic anhydrase inhibition and brain electrolyte composition. Am J Physiol 1960; 198: 434-40.

48. Rho JM, Sankar R. The pharmacologic basis of antiepileptic drug action. Epilepsia 1999; 40: 1471-83.

49. Traynelis SF, Cull-Candy SG. Proton inhibition of N-methyl-D-aspartate receptors in cerebellar neurons. Nature 1990; 345: 347-50.

50. Krishek BJ, Amato A, Connolly CN, Moss SJ, Smart TG. Proton sensitivity of the GABAA receptor is associated with the receptor subunit composition. J Physiol 1996; 492: 431-43.

51. Staley KJ, Soldo BL, Proctor WR. Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. Science 1995; 269: 977-81.

52. Jung MJ, Lippert B, Metcalf B, et al. gamma-Vinyl GABA (4-amino-hex-5-enoic acid), a new irreversible inhibitor of GABA-T: effects on brain GABA metabolism in mice. J Neurochem 1977; 29: 797-802.

53. Schechter PJ, Tranier Y, Jung MJ, et al. Audiogenic seizure protection by elevated brain GABA concentration in mice: effects of gamma-acetylenic GABA and gamma-vinyl GABA, two irreversible GABA-T inhibitors. Eur J Pharmacol 1977; 45: 319-28.

54. Petroff OAC, Rothman DL, Behar KL, et al. Human brain GABA levels rise after initiation of vigabatrin therapy but fail to rise further with increasing dose. Neurology 1996; 46: 1459-63.

55. Petroff OAC, Rothman DL. Measuring human brain GABA in vivo: effects of GABA-transaminase inhibition with vigabatrin. Mol Neurobiol 1998; 16: 97-121.

56. Leach JP, Sills GJ, Majid A, et al. Effects of tiagabine and vigabatrin on GABA uptake into rat cortical astrocytes in primary culture. Seizure 1996; 5: 229-34.

57. Cheung H, Kamp D, Harris E. An in vitro investigation of the action of lamotrigine on neuronal voltage-activated sodium channels. Epilepsy Res 1992; 13: 107-12.

58. Lang DG, Wang CM, Cooper BR. Lamotrigine, phenytoin and carbamazepine interactions on the sodium current present in N4TG1 mouse neuroblastoma cells. J Pharmacol Exp Ther 1993; 266: 829-35.

59. Wang CM, Lang DG, Cooper BR. Lamotrigine effects on ion channels in cultured neuronal cells. Epilepsia 1993; 34 (suppl 6): 117-8.

60. Zona C, Avoli M. Lamotrigine reduces voltage-gated sodium currents in rat central neurons in culture. Epilepsia 1997; 38: 522-5.

61. Kuo CC, Lu L. Characterization of lamotrigine inhibition of Na+ channels in rat hippocampal neurones. Br J Pharmacol 1997; 121: 1231-8.

62. Leach MJ, Marden CM, Miller AA. Pharmacological studies on lamotrigine, a novel potential antiepileptic drug: II. Neurochemical studies on the mechanism of action. Epilepsia 1986; 27: 490-7.

63. Stefani A, Spadoni F, Siniscalchi A, et al. Lamotrigine inhibits Ca2+ currents in cortical neurons: functional implications. Eur J Pharmacol 1996; 307: 113-6.

64. Wang SJ, Huang CC, Hsu KS, et al. Inhibition of N-type calcium currents by lamotrigine in rat amygdalar neurones. Neuroreport 1996; 7: 3037-40.

65. Stefani A, Spadoni F, Bernardi G. Voltage-activated calcium channels: targets of antiepileptic drug therapy? Epilepsia 1997; 38: 959-65.

66. Teoh H, Fowler LJ, Bowery NG. Effect of lamotrigine on the electrically-evoked release of endogenous amino acids from slices of dorsal horn of the rat spinal cord. Neuropharmacology 1995; 34: 1273-8.

67. Taylor LA, McQuade RD, Tice MA. Felbamate, a novel antiepileptic drug, reverses N-methyl-D-aspartate/glycine-stimulated increases in intracellular Ca2+ concentration. Eur J Pharmacol 1995; 289: 229-33.

68. Pisani A, Stefani A, Siniscalchi A, et al. Electrophysiological actions of felbamate on rat striatal neurones. Br J Pharmacol 1995; 16: 2053-61.

69. Pugliese AM, Corradetti R. Effects of the antiepileptic drug felbamate on long-term potentiation in the CA1 region of rat hippocampal slices. Neurosci Lett 1996; 215: 21-4.

70. McCabe RT, Wasterlain CG, Kucharczyk N, et al. Evidence of anticonvulsant and neuroprotective action of felbamate mediated by strychnine-insensitive glycine receptors. J Pharmacol Exp Ther 1993; 264: 248-52.

71. White HS, Harmsworth WL, Sofia RD, et al. Felbamate modulates the strychnine-insensitive glycine receptor. Epilepsy Res 1995; 20: 41-8.

72. Rho JM, Donevan SD, Rogawski MA. Mechanism of action of the anticonvulsant felbamate: opposing effects on N-methyl-D-aspartate and gamma-aminobutyric acid receptors. Ann Neurol 1994; 35: 229-34.

73. Ticku MK, Kamatchi GL, Sofia RD. Effect of anticonvulsant felbamate on GABA receptor system. Epilepsia 1991; 32: 389-91.

74. Rho JM, Donevan SD, Rogawski MA. Barbiturate-like actions of the propanediol dicarbamates felbamate and meprobamate. J Pharmacol Exp Ther 1997; 280: 1383-91.

75. Taglialatela M, Ongini E, Brown AM, et al. Felbamate inhibits cloned voltage-dependent Na+ channels from human and rat brain. Eur J Pharmacol 1996; 316: 373-7.

76. Stefani A, Calabresi P, Pisani A, et al. Felbamate inhibits dihydropyridine-sensitive calcium channels in central neurons. J Pharmacol Exp Ther 1996; 277: 121-7.

77. Srinivasan J, Richens A, Davies JA. Effects of felbamate on veratridine- and K+-stimulated release of glutamate from mouse cortex. Eur J Pharmacol 1996; 315: 285-8.

78. Taylor CP, Vartanian MG, Andruszkiewicz R, et al. 3-alkyl GABA and 3-alkylglutamic acid analogues: two new classes of anticonvulsant agents. Epilepsy Res 1992; 11: 103-10.

79. Gotz E, Feuerstein TJ, Meyer DK. Effects of gabapentin on release of gamma-aminobutyric acid from slices of rat neostriatum. Drug Res 1993; 43: 636-8.

80. Leach JP, Sills GJ, Butler E, et al. Neurochemical actions of gabapentin in mouse brain. Epilepsy Res 1997; 27: 175-80.

81. Taylor CP, Gee NS, Su TZ, et al. A summary of mechanistic hypotheses of gabapentin pharmacology. Epilepsy Res 1998; 29: 233-49.

82. Su TZ, Lunney E, Campbell G, et al. Transport of gabapentin, a gamma-amino acid drug, by system l alpha-amino acid transporters: a comparative study in astrocytes, synaptosomes, and CHO cells. J Neurochem 1995; 64: 2125-31.

83. Macdonald RL, Greenfield LJ, Jr. Mechanisms of action of new antiepileptic drugs. Curr Opin Neurol 1997; 10: 121-8.

84. Petroff OAC, Rothman DL, Behar KL, et al. The effect of gabapentin on brain gamma-aminobutyric acid in patients with epilepsy. Ann Neurol 1996; 39: 95-9.

85. Gee NS, Brown JP, Dissanayake VUK, et al. The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. J Biol Chem 1996; 271: 5768-76.

86. Stefani A, Spadoni F, Giacomini P, Lavaroni F, Bernardi G. The effects of gabapentin on different ligand- and voltage-gated currents in isolated cortical neurons. Epilepsy Res 2001; 43: 239-48.

87. Goldlust A, Su T, Welty DF, et al. Effects of the anticonvulsant drug gabapentin on enzymes in the metabolic pathways of glutamate and GABA. Epilepsy Res 1995; 22: 1-11.

88. Wamil AW, McLean MJ. Limitation by gabapentin of high frequency action potential firing by mouse central neurons in culture. Epilepsy Res 1994; 17: 1-11.

89. Shank RP, Gardocki JF, Vaught JL, et al. Topiramate: preclinical evaluation of a structurally novel anticonvulsant. Epilepsia 1994; 35: 450-60.

90. Zona C, Ciotti MT, Avoli M. Topiramate attenuates voltage-gated sodium currents in rat cerebellar granule cells. Neurosci Lett 1996; 231: 123-6.

91. Zona C, Barbarosie M, Kawasaki H, et al. Effects induced by the anticonvulsant drug topiramate on voltage-gated sodium currents generated by cerebellar granule cells in tissue culture. Epilepsia 1996; 37 (suppl 5): 24.

92. DeLorenzo RJ, Sombati S, Coulter DA. Effects of topiramate on sustained repetitive firing and spontaneous recurrent seizure discharges in cultured hippocampal neurons. Epilepsia 2000; 41 (suppl 1): S40-44.

93. Zhang X, Velumian AA, Jones OT, et al. Modulation of high-voltage-activated calcium channels in dentate granule cells by topiramate. Epilepsia 2000; 41 (suppl 1): S52-60.

94. White HS, Brown SD, Woodhead JH, et al. Topiramate enhances GABA-mediated chloride flux and GABA-evoked chloride currents in murine brain neurons and increases seizure threshold. Epilepsy Res 1997; 28: 167-79.

95. Gibbs III, JW Sombati S, DeLorenzo RJ, et al. Cellular actions of topiramate: blockade of kainate-evoked inward currents in cultured hippocampal neurons. Epilepsia 2000; 41 (suppl 1): S10-16.

96. Petroff OAC, Hyder F, Mattson RH, et al. Topiramate increases brain GABA, homocarnosine, and pyrrolidinone in patients with epilepsy. Neurology 1999; 52: 473-8.

97. Sills GJ, Leach JP, Kilpatrick WS, et al. Concentration-effect studies with topiramate on selected enzymes and intermediates of the GABA shunt. Epilepsia 2000; 41 (suppl 1): S30-34.

98. Editorial. Oxcarbazepine. Lancet 1989; ii: 196-8.

99. McLean MJ, Schmutz M, Wamil AW, et al. Oxcarbazepine: mechanisms of action. Epilepsia 1994; 35 (suppl 3): S5-9.

100. Calabresi P, De Murtas M, Stefani A, et al. Action of GP 47779, the active metabolite of oxcarbazepine, on the corticostriatal system. I. Modulation of corticostriatal synaptic transmission. Epilepsia 1995; 36: 990-6.

101. Stefani A, Pisani A, De Murtas M, et al. Action of GP 47779, the active metabolite of oxcarbazepine, on the corticostriatal system. II. Modulation of high-voltage-activated calcium currents. Epilepsia 1995; 336: 997-1002.

102. Suzdak PD, Jansen JA. A review of the preclinical pharmacology of tiagabine: a potent and selective anticonvulsant GABA uptake inhibitor. Epilepsia 1995; 36: 612-26.

103. Braestrup C, Nielsen GB, Sonnewald U, et al. (R)-N-[4,4-bis(3-methyl-2-thienyl)but-3-en-1-yl] nipecotic acid binds with high affinity to the brain g-aminobutyric acid uptake carrier. J Neurochem 1990; 54: 639-47.

104. Borden LA, Dhar TGM, Smith KE, et al. Tiagabine, SKF 89976-A, CI-966, and NNC-711 are selective for cloned GABA transporter GAT-1. Eur J Pharmacol 1994; 269: 219-24.

105. Sills GJ, Butler E, Thompson GG, et al. Vigabatrin and tiagabine are pharmacologically different drugs. A pre-clinical study. Seizure 1999; 8: 404-11.

106. Roepstorff, Lambert JD. Comparison of the effect of GABA uptake blockers, tiagabine and nipecotic acid, on inhibitory synaptic efficacy in hippocampal CA1 neurones. Neurosci Lett 1992; 146: 131-4.

107. Brodie MJ. Tiagabine pharmacology in profile. Epilepsia 1995; 36 (suppl 6): S7-9.

108. Genton P, Van Vleymen B. Piracetam and levetiracetam: close structural similarities but different pharmacological and clinical profiles. Epileptic Disord 2000; 2: 99-105.

109. Noyer M, Gillard M, Matagne A, et al. The novel antiepileptic drug levetiracetam (ucb L059) appears to act via a specific binding site in CNS membranes. Eur J Pharmacol 1995; 286: 137-46.

110. Sills GJ, Leach JP, Fraser CM, et al. Neurochemical studies with the novel anticonvulsant levetiracetam in mouse brain. Eur J Pharmacol 1997; 325: 35-40.

111. Löscher W, Hönack D, Bloms-Funke P. The novel antiepileptic drug levetiracetam (ucb L059) induces alterations in GABA metabolism and turnover in discrete areas of rat brain and reduces neuronal activity in substantia nigra pars reticulata. Brain Res 1996; 735: 208-16.

112. Margineanu DG, Wulfert E. ucb L059, a novel anticonvulsant, reduces bicuculline-induced hyperexcitability in rat hippocampal CA3 in vivo. Eur J Pharmacol 1995; 286: 321-5.

113. Margineanu DG, Wulfert E. Inhibition by levetiracetam of a non-GABAA receptor-associated epileptiform effect of bicuculline in rat hippocampus. Br J Pharmacol 1997; 122: 1146-50.

114. Birnstiel S, Wulfert E, Beck SG. Levetiracetam (ucb L059) affects in vitro models of epilepsy in CA3 pyramidal neurons without altering normal synaptic transmission. Naunyn-Schmiedebergs Arch Pharmacol 1997; 356: 611-8.

115. Zona C, Niespodziany I, Marchetti C, Klitgaard H, Bernardi G, Margineanu DG. Levetiracetam does not modulate neuronal voltage-gated Na+ and T-type Ca2+ currents. Seizure 2001; 10: 279-86.

116. Niespodziany I, Klitgaard H, Margineanu DG. Levetiracetam inhibits the high-voltage-activated Ca2+ current in pyramidal neurones of rat hippocampal slices. Neurosci Lett 2001; 306: 5-8.

117. Schauf CL. Zonisamide enhances slow sodium inactivation in Myxicola. Brain Res 1987; 413: 185-8.

118. Rock DM, Macdonald RL, Taylor CP. Blockade of sustained repetitive action potentials in cultured spinal cord neurons by zonisamide (AD 810, CI 912): a novel anticonvulsant. Epilepsy Res 1989; 3: 138-43.

119. Suzuki S, Kawakami K, Nishimura S, et al. Zonisamide blocks T-type calcium channels in cultured neurons of rat cerebral cortex. Epilepsy Res 1992; 12: 21-7.

120. Mimaki T, Suzuki Y, Tagawa T, et al. [3H]zonisamide binding in rat brain. Jap J Psychiat Neurol 1988; 42: 640-2.

121. Kawata Y, Okada M, Murakami T, et al. Effects of zonisamide on K+ and Ca2+ evoked release of monoamine as well as K+ evoked intracellular Ca2+ mobilization in rat hippocampus. Epilepsy Res 1999; 35: 173-82.

122. Okada M, Kaneko S, Hirano T, et al. Effects of zonisamide on dopaminergic system. Epilepsy Res 1995; 22: 193-205.

123. Kwan P, Brodie MJ. Early identification of refractory epilepsy. N Engl J Med 2000; 342: 314-9.

124. Kwan P, Brodie MJ. Epilepsy after the first drug fails: substitution or add-on? Seizure 2000; 9: 464-8.