Mechanisms of action of new antiepileptic drugs

Current Opinion in Neurology

Volumn 10, Issue 2, 1997, Pages 121-128

  Macdonald, Robert L ^a,b   Greenfield Jr , L John ^a  

^a UNIVERSITY OF MICHIGAN HEALTH SYSTEM   (United States)

^b Neuroscience Laboratory Building   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 AMINOBUTYRIC ACID; 4 AMINOBUTYRIC ACID A RECEPTOR; ANTICONVULSIVE AGENT; CALCIUM CHANNEL; FELBAMATE; GABAPENTIN; GLUTAMATE RECEPTOR; GLUTAMIC ACID; LAMOTRIGINE; OXCARBAZEPINE; SODIUM CHANNEL; TIAGABINE; TOPIRAMATE; VIGABATRIN;

ANTICONVULSANT ACTIVITY; ARTICLE; CHANNEL GATING; EPILEPSY; EXCITABILITY; HUMAN; NEUROTRANSMISSION; SEIZURE;

EID: 0030959522     PISSN: 13507540     EISSN: None     Source Type: Journal    
DOI: 10.1097/00019052-199704000-00009     Document Type: Article

References (99)

1. Macdonald RL, Kelly KM: Mechanisms of action of currently prescribed and newly developed antiepileptic drugs. Epilepsia 1994, 35(suppl 4):S41-S50.
2. Upton N: Mechanisms of action of new antiepileptic drugs: rational design and serendipitous findings. Trends Pharmacol Sci 1994, 15:456-463.
3. Reynolds EH, Milner G, Matthews DM, Chanarin I: Antlconvulsant therapy, megaloblastic haemopoiesis and folic acid metabolism. Q J Med 1966, 35:521-537.
4. Rogowski M, Porter R: Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev 1990, 42:223-286.
5. Leach MJ, Marden CM, Miller AA: Pharmacological studies on lamotrigine, a novel potential antieplleptic drug: II. Neurochemical studies on the mechanism of action. Epilepsia 1986, 27:490-497.
6. Cheung H, Kamp D, Harris E: An in vitro investigation of the action of lamotrigine on neuronal voltage-activated sodium channels. Epilepsy Res 1992, 13:107-112.
7. + channels in rat hippocampal neurones. Pflügers Arch 1995, 430:437-446. This elegant study demonstrates the effect of lamotrigine both on recombinant rat brain sodium channels and on the action potentials of rat hippocampal neurons, showing an action at the inactivated form of the channel.
8. McLean MJ, Macdonald RL: Multiple actions of phenytoin on mouse spinal cord neurons in cell cultures. J Pharmacol Exp Ther 1983, 227:779-789.
9. McLean MJ, Macdonald RL: Carbamazepine and 10,11-epoxycarbamazepine produce use- and voltage-dependent limitation of rapidly firing action potentials of mouse central neurons in cell culture. J Pharmacol Exp Ther 1986, 238:727-732.
10. 2+ currents in cortical neurons: functional implications. Eur J Pharmacol 1996, 307:113-116. This is one of several recent papers in which this group demonstrates inhibition of high voltage-activated calcium currents by conventional and novel anticonvulsants.
11. Wang SJ, Huang CC, Hsu KS, Tsai JJ, Gean PW: Presynaptic inhibition of excitatory neurotransmission by lamotrigine in the rat amygdalar neurons. Synapse 1996, 24:248-255.
12. Casanovas A, Ribera J, Hukkanen M, Riveros-Moreno V, Esquerda JE: Prevention by lamotrigine, MK801 and N-omega-nitro-L-arglnine methyl ester of motoneuron cell death after neuronal axotomy. Neuroscience 1996, 71:313-325.
13. Shuaib A, Mahmood RH, Wishart T, Kanthan R, Murabit MA, Ijaz S, Miyashita H, Howlett W: Neuroprotective effects of lamotrigine in global ischemla in gerblls. A histological in vivo mlcrodlalysis and behavioral study. Brain Res 1995, 702:199-206.
14. Waldmeier PC, Martin P, Stocklin K, Portet C, Schmutz M: Effect of • carbamazepine, oxcarbazepine and lamotrigine on the increase in extracellular glutamate elicited by veratridine in rat cortex and striatum. Naunyn-Schmiedeberg's Arch Pharmacol 1996, 354:164-172. This paper calls into question the issue of selective inhibition of glutamate release as an anticonvulsant mechanism for AEDs that act at the sodium channel.
15. Jensen PK, Gram L, Schmutz M: Oxcarbazepine. Epilepsy Res 1991, 3(suppl):135-140.
16. Dam M, Jensen PK: Potential antieplleptic drugs: oxcarbazepine. In Antiepileptic drugs, edn 3. Edited by Levy RH, Dreyfus FE, Mattson RH, Meldrum BS, Penry JK. New York: Raven Press; 1989:913-924.
17. Schmutz M, Ferret T, Heckendorn R, Jeker A, Portet C, Olpe HR: GP47779, the main human metabolite of oxcarbazepine (Trlleptal), and both enantiomers have equal anticonvulsant activity [Abstract]. Epilepsia 1993, 34(suppl 2):122.
18. McLean MJ, Schmutz M, Wamil AW, Olpe HR, Portet C, Feldmann KF: Oxcarbazepine: mechanisms of action. Epilepsia 1994, 35(suppl 3):S5-S9.
19. Calabresi P, De Murtas M, Stefani A, Pisani A, Sancesario G, Mercuri NB, Bernardi G: Action of GP 47779, the active metabolite of oxcarbazepine, on the cortlcostriatal system. I. Modulation of cortlcostriatal synaptlc transmission. Epilepsia 1995, 36:990-996.
20. Stefani A, Pisani A, De Murtas M, Mercuri NB, Marciani MG, Calabresi P: Action of GP 47779, the active metabolite of oxcarbazeplne, on the corticostriatal system. II. Modulation of high-voltage-activated calclum currents. Epilepsia 1995, 336:997-1002.
21. Faught E, Wilder BJ, Ramsey RE, Reife RA, Kramer LD, Pledger GW, Karim RM, Topiramate YD Study Group: Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 200-, 400-, and 600-mg daily dosages. Neurology 1996, 46:1684-1690.
22. Privatera M, Fincham R, Penry J, Reife R, Kramer L, Pledger G, Karim R, Topiramate YD Study Group. Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 600-, 800-, and 1000-mg daily dosages. Neurology 1996, 46:1678-1683.
23. Coulter DA, Sombati S, Delorenzo RJ: Selective effects of topiramate on sustained repetitive firing and spontaneous bursting in cultured hippocampal neurons [Abstract]. Epilepsia 1993, 34(suppl 2):123.
24. Kawasaki H, Lopantsev V, Zona C, Avoli M: Topiramate depresses intrinsic bursts in the rat subiculum in vitro [Abstract]. Epilepsia 1996, 37(suppl 5):26.
25. Zona C, Barbarosie M, Kawasaki H, Avoli M: Effects induced by the anticonvulsant drug topiramate on voltage-gated sodium currents generated by cerebellar granule cells in tissue culture [Abstract]. Epilepsia 1996, 37(suppl 5):24.
26. Kanda T, Kurokawa M, Tamura S, Nakamura J, Ishii A, Kuwana Y, • Serikawa T, Yamada J, Ishihara K, Sasa M: Toplramate reduces abnormally high extracellular levels of glutamate and aspartate in the hippocampus of spontaneously epileptic rats. Life Sci 1996, 59:1607-1616. The spontaneously epileptic rat was developed from the Wistar strain as a model of tonic and absence seizures, and was found by microdialysis to have abnormally high levels of excitatory amino acid transmitters. Topiramate reduced these levels in spontaneously epileptic rats without affecting levels in wild-type animals, probably through presynaptic action at the sodium channel.
27. Brown SD, Wolf HH, Swinyard EA, Twyman RE, White HS: The novel anticonvulsant toplramate enhances GABA-medlated chloride flux. Epilepsia 1993, 34(suppl 2):122-123.
28. White HS, Brown D, Skeen GA, Wolf HH, Twyman RE: The anticonvulsant topiramate displays a unique ability to potentiate GABA-evoked chloride currents. Epilepsia 1995, 36(suppl 3):39-40.
29. White HS, Woodhead JH, Wolf HH: Effect of topiramate (TPM) on pentylenetetrazol (PTZ) seizure threshold [Abstract]. Epilepsia 1996, 37(suppl 5):26.
30. Nakamura J, Tamura S, Kanda T, Ishii A, Ishihara K, Serikawa T, Yamada J, Sasa M: Inhibition by topiramate of seizures in spontaneously epileptic rats and DBA/2 mice. Eur J Pharmacol 1994, 254:83-89.
31. Bauer G, Bechinger D, Castell M: Gabapentin in the treatment of drug-resistant epileptic patients. Adv Epileptol 1989, 219-221.
32. Rowen AJ, Schear MJ, Weiner JA, Luciano D: Intensive monitoring and pharmacokinetic studies of gabapentin in patients with generalized spike-wave discharges. Epilepsia 1989, 30:30.
33. Schmidt D: Potential antiepileptic drugs: gabapentin. In Antiepileptic drugs, edn 3. Edited by Levy RH, Dreyfus FE, Mattson RH, Meldrum BS, Penry JK. New York: Raven Press; 1989:925-935.
34. Bartoszyk GD, Reimann W: Preclinical characterization of the anticonvulsant gabapentin. 16th Epilepsy International Congress, Hamburg, Germany, 1985.
35. Reimann W: Inhibition by GABA, baclofen and gabapentin of dopamine release from rat caudate nucleus: are there common or different sites of action? Eur J Pharmacol 1983, 94:341-344.
36. Schlicker PJ, Reimann W, Gothert M: Gabapentin decreases monoamine release without affecting acetylcholine release in the brain. Arzneim.-Forsch./Drug Res 1985, 35:1347-1349.
37. Bartoszyk GD, Meyerson N, Reimann W, Satzinger G, von Hodenberg A: Gabapentin. In Current problems in epilepsy. Edited by Meldrum BS, Porter RJ. London: John Libbey & Company; 1986:147-164.
38. Rock DM, Kelly KM, Macdonald RL: Gabapentin actions on ligand- and voltage-gated responses in cultured rodent neurons. Epilepsy Res 1993, 16:89-98.
39. Dooley DJ, Bartoszyk GD, Rock DM, Satzinger G: Preclinical characterization of the anticonvulsant gabapentin. 16th Epilepsy International Congress. Hamburg, 1985.
40. Taylor CP, Rock DM, Weinkauf RJ, Ganong AH: In vitro and in vivo electrophysiology effects of the anticonvulsant gabapentin. Soc Neurosci Abstr 1988, 14:866.
41. •].
42. •] provide evidence for a novel mechanism of action for gabapentin: the enhancement of nonvesicular stimulated release of GABA. Although the methodology is complex, making interpretation difficult, these studies suggest that gabapentin may increase the synthesis and release of GABA with increased neuronal activity, when greater release is desirable (i.e. during a seizure).
43. Bartoszyk GD: Gabapentin and convulsions provoked by excitatory amino acids [Abstract]. Naunyn-Schmiedeberg's Arch Pharmacol 1983, 324:R94.
44. Oles RJ, Singh L, Hughes J, Woodruff GN: The anticonvulsant action of gabapentin involves the glycine NMDA receptor. Soc Neurosci Abstr 1990, 16:783.
45. Löscher W, Honack D, Taylor CP: Gabapentin increases aminooxyacetic acid-induced GABA accumulation in several regions of rat brain. Neurosci Lett 1991, 128:150-154.
46. Petroff OAC, Rothman DL, Behar KL, Lamoureux D, Mattson RH: The effect of gabapentin on brain gamma-aminobutyric acid in patients with epilepsy. Ann Neurol 1996, 39:95-99.
47. Goldlust A, Su TZ, Welty DF, Taylor CP, Oxender DL: Effects of anticonvulsant drug gabapentin on the enzymes in metabolic pathways of glutamate and GABA. Epilepsy Res 1995, 22:1-11.
48. Thurlow RJ, Hill DR, Woodruff GN: Comparison of the uptake of [3H]-gabapentin with the uptake of L-[3H]-leucine into rat brain synaptosomes. Br J Pharmacol 1996, 118:449-456.
49. Thurlow RJ, Hill DR, Woodruff GN: Comparison of the autoradiographic binding distribution of [3H]-gabapentin with excitatory amino acid receptor and amino acid uptake site distributions in rat brain. Br J Phamacol 1996, 118:457-465.
50. Taylor CP, Vartanian MG, Yuen PW, Bigge C: Potent and stereospecific anticonvulsant activity of 3-isobutyl GABA relates to in vitro binding at a novel site labeled by tritiated gabapentin. Epilepsy Res 1993, 14:11-15.
51. 2+ channel protein confirmed the affinity of gabapentin for this channel.
52. Wamil AW, McLean MJ, Taylor CP: Multiple cellular actions of gabapentin [Abstract]. Neurology 1991, 41(suppl 1):140.
53. Wamil AW, McLean MJ: Limitation by gabapentin of high frequency action potential firing by mouse central neurons in cell culture. Epilepsy Res 1994, 17:1-10.
54. + channels in a voltage-dependent manner but gabapentin does not. Soc Neurosci Abstr 1993, 19:1631.
55. Aicardi J, Hauser E, Steinbock H, Szyper M, Holsteen V, Ostergaard J, Pedersen SA, Taudorf K, Barthez-Carpentier MA, Badinand-Hubert N et al.: Vigabatrin as initial therapy for infantile spasms. Epilepsia 1996, 37:638-642.
56. Jung MJ, Lippert B, Metcalf B, Bohlen P, Schechter PJ: γ-vinyl GABA (4-amino-hex-5-enoic acid), a new Irreverslble inhibitor of GABA-T: effects on brain GABA metabolism in mice. J Neurochem 1977, 29:797-802.
57. Schechter PJ, Trainer Y: Effects of elevated brain GABA concentrations on the action of blcuculline and picrotoxin in mice. Psychopharmacology 1977, 45:319-328.
58. Sarhan S, Seiler N: Metabolic inhibitors and subcellular distribution of GABA. J Neurosci Res 1979, 4:399-421.
59. Schoesboe A, Larsson OM, Seiler N: Stereoselective uptake of the GABA-transaminase inhibitors gamma-vinyl GABA and gamma-acetylenlc GABA into neurons and astrocytes. Neurochem Res 1986, 11:1497-1505.
60. Preece NE, Cerdan S: Metabolic precursors and compartmentation of cerebral GABA in vigabatrin-treated rats. J Neurochem 1996, 67:1718-1725.
61. 13C]glucose is reduced in rats treated with the GABA-transaminase inhibitor vigabatrin (gamma-vinyl GABA). Neurochem Res 1996, 21:1031-1041.
62. Schmid L, Bottlaender M, Brouillet E, Fuseau C, Mazière M: Vigabatrin modulates benzodiazepine receptor activity in vivo. J Pharmacol Exp Therap 1996, 276:977-983.
63. Grove J, Schechter PJ, Tell G: Increased gamma-aminobutyric acid (GABA), homocarnosine and β-alanine in cerebrospinal fluid of patients treated with gamma-vinyl GABA (4-amino-hex-5-enolc acid). Life Sci 1981, 28:2431-2439.
64. Schechter PJ, Hanke NFJ, Grove J, Huebert N, Sjoerdsma A: Biochemical and clinical effects of gamma-vinyl GABA in patients with epilepsy. Neurology 1984, 34:182-186.
65. Ben-Menachem E: Pharmacokinetic effects of vigabatrin on cerebrospinal fluid amino acids in humans. Epilepsia 1989, 30(suppl 3): S12-S14.
66. Reikkenen PJ, Pitkänen A, Ylinen A, Sivenius J, Halonen T: Specificity of vigabatrin for the GABAergic system in human epilepsy. Eur J Pharmacol 1989, 94:341-344.
67. Petroff OAC, Rothman DL, Behar KL, Mattson RH: Effect of vigabatrin on GABA levels in human brain measured in vivo with [1H] NMR spectroscopy [Abstract]. Epilepsia 1993, 34(suppl 6):68.
68. Petroff OAC, Rothman DL, Behar KL, Mattson RH: Human brain GABA levels rise after initiation of vigabatrin therapy but fail to rise further with increasing dose. Neurology 1996, 46:1459-1463.
69. Pitkänen A, Tuunanen J, Halonen T: Vigabatrin and carbamazepine have different efficacies in the prevention of status epilepticusinduced neuronal damage in the hippocampus and amygdala. Epilepsy Res 1996, 24:29-45.
70. Braestrup C, Nielsen EB, Sonnewald U, Knutsen LJ, Andersen KE, Jansen JA, Frederiksen K, Andersen PH, Mortensen A, Suzdak PD: R(-)-N-[4,4-di(3-methyl-thien-2-yl)-but-3-en-1-yl]nipecotic acid binds with high affinity to the brain γ-aminobutyric acid uptake carrier. J Neurochem 1990, 54:639-648.
71. Suzdak PD, Jansen JA: A review of the preclinical pharmacology of tiagabine: a potent and selective anticonvulsant GABA uptake inhibitor. Epilepsia 1995, 36:612-626.
72. Fink-Jensen A, Suzdak RD, Sweberg MD, Judge ME, Hansen L, Nielsen PG: The GABA uptake inhibitor, tiagabine, increases extra-cellular brain levels of GABA in awake rats. Eur J Pharmacol 1992, 220:197-201
73. 3H]tiagabine binding to sections from mice brain. Epilepsy Res 1995, 21:79-88.
74. Roepstorff A, Lambert JDC: Comparison of the effect of the GABA uptake blockers, tiagabine and nipecotic acid, on inhibitory synaptic efficacy In hlppocampal CA1 neurones. Neurosci Lett 1992, 146:131-134.
75. Halonen T, Nissinen J, Jansen JA, Pitkänen A: Tiagabine prevents seizures, neuronal damage and memory impairment in experimental status epilepticus. Eur J Pharmacol 1996, 299:69-81.
76. Inglefield JR, Perry JM, Schwartz RD: Postischemic inhibition of GABA reuptake by tiagabine slows neuronal death in the gerbil hippocampus. Hippocampus 1995, 5:460-468.
77. Vergnes M, Marescaux C, Micheletti G, Depaulis A, Rumbach L, Warter JM: Enhancement of spike and wave discharges by GABA mimetic drugs in rats with spontaneous petit mal-like epilepsy. Neurosci Lett 1984, 44:91-94.
78. Peeters BWMM, van Rijn CM, Vossen JMH, Coenen AML: Effects of GABAergic agents in spontaneous non-convulsive epilepsy, EEG and behaviour, in the WAG/Rij inbred strain of rats. Life Sci 1989, 45:1171-1176.
79. Coenen AML, Blezer EHM, van Luijtelaar ELJM: Effects of the GABA • uptake inhibitor tiagabine on electroencephalogram, spike-wave discharges and behaviour of rats. Epilepsy Res 1995, 21:89-94. This study confirms the finding that tiagabine, and perhaps other AEDs that elevate central nervous system GABA levels, may exacerbate seizures and epileptiform activity in models of nonconvulsive generalized absence epilepsy.
80. Walton NY, Gunawan S, Treiman DM: Treatment of experimental status epilepticus with the GABA uptake inhibitor, tiagabine. Epilepsy Res 1994, 19:237-244.
81. Stables JP, Bialer M, Johannessen SI, Kupferberg HJ, Levy RH, Loiseau P, Perucca E: Progress report on new antiepileptic drugs: a summary of the Second Eilat Conference. Epilepsy Res 1995, 22:235-246.
82. Gordon R, Gels M, Diamantis W, Sofia RD: Interaction of felbamate and diazepam against maximal electroshock seizures and chemoconvulsants in mice. Pharmacol Biochem Behav 1991, 40:109-113.
83. A receptor system. Epilepsia 1991, 32:389-391.
84. A receptors. Ann Neurol 1994, 35:229-234.
85. A receptor currents by felbamate at a possibly novel site.
86. Sofia RD, Kramer L, Perhach JL, Rosenberg A: Felbamate. In New antiepileptic drugs. Edited by Pisani F, Perucca E, Avanzini G, Richens A. Amsterdam: Elsevier; 1991:103-108.
87. Harmsworth WL, Wolf HH, Swinyard EA, White HS: Felbamate modulates glycine receptor function. Epilepsia 1993, 34(suppl 2):92-93.
88. McCabe RT, Wasterlain CG, Kucharczyk N, Sofia RD, Vogel JR: Evidence of anticonvulsant and neuroprotective action of felbamate mediated by strychnine-insensitive glycine receptors. J Pharmacol Exp Ther 1993, 264:248-252.
89. Pisani A, Stefani A, Siniscalchi A, Mercuri NB, Bernardi G, Calabresi P: • Electrophysiological actions of felbamate on rat striatal neurones. Br J Pharmacol 1995, 116:2053-2061. This study demonstrates a physiologic effect of felbamate on corticostriatal excitatory neurotransmission at NMDA receptors in the slice preparation, but also suggests a presynaptic effect on sodium channels to reduce repetitive action potential firing.
90. Pugliese AM, Corradetti R: Effects of the antiepileptic drug felbamate on long term potentiation in the CA1 region of rat hippocampal slices. Neurosci Leff 1996, 215:21-24.
91. White HS, Wolf HH, Swinyard EA, Skeen GA, Sofia RD: A neuropharmacologic evaluation of felbamate as a novel anticonvulsant [Abstract]. Epilepsia 1992, 33:564.
92. Libri V, Constanti A, Zibetti M, Nistico S: Effects of felbamate on muscarinic and metabotropic glutamate agonist-mediated responses and magnesium-free or 4-aminopyridine-induced epileptiform activity in guinea pig olfactory cortex neurons in vitro. J Pharmacol Exp Ther 1996, 277:1759-1769.
93. Stefani A, Calabresi P, Pisani A, Mercuri NB, Siniscalchi A, Bernardi G: Felbamate inhibits dihydropyridine-sensitive calcium channels in central neurons. J Pharmacol Exp Ther 1996, 277:121-127.
94. Shuaib A, Waqaar T, Ijaz MS, Kanthan R, Wishart T, Howlett W: Neuroprotection with felbamate: A7- and 28-day study in transient forebrain ischemia in gerbils. Brain Res 1996, 727:65-70.
95. Wasterlain CG, Adams LM, Wichmann JK, Sofia RD: Felbamate protects CA1 neurons from apoptosis in a gerbil model of global ischemia. Stroke 1996, 27:1236-1240.
96. Wallis RA, Panizzon KL: Felbamate neuroprotection against CA1 traumatic neuronal injury. Eur J Pharmacol 1995, 294:475-482.
97. Chronopoulos A, Stafstrom C, Thurber S, Hyde P, Mikati M, Holmes GL: Neuroprotective effect of felbamate after kalnic acid-induced status epilepticus. Epilepsia 1993, 34:359-366.
98. Kanthasamy AG, Matsumoto RR. Gunasekar PG, Truong DD: Excitoprotective effect of felbamate in cultured cortical neurons. Brain Res 1995, 705:97-104.
99. Lynch MW, Rutecki PA, Sutula TP: The effects of seizures on the brain. Curr Opin Neurol 1996, 9:97-102.