Neurochemical Research

, Volume 27, Issue 1–2, pp 121–130

Mechanisms of Action of Carbamazepine and Its Derivatives, Oxcarbazepine, BIA 2-093, and BIA 2-024

  • António F. Ambrósio
  • Patrício Soares-da-Silva
  • Caetana M. Carvalho
  • Arsélio P. Carvalho


Carbamazepine (CBZ) has been extensively used in the treatment of epilepsy, as well as in the treatment of neuropathic pain and affective disorders. However, the mechanisms of action of this drug are not completely elucidated and are still a matter of debate. Since CBZ is not very effective in some epileptic patients and may cause several adverse effects, several antiepileptic drugs have been developed by structural variation of CBZ, such as oxcarbazepine (OXC), which is used in the treatment of epilepsy since 1990. (S)-(−)-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine-5-carboxamide (BIA 2-093) and 10,11-dihydro-10-hydroxyimino-5H-dibenz[b,f]azepine-5-carboxamide (BIA 2-024), which were recently developed by BIAL, are new putative antiepileptic drugs, with some improved properties. In this review, we will focus on the mechanisms of action of CBZ and its derivatives, OXC, BIA 2-093 and BIA 2-024. The available data indicate that the anticonvulsant efficacy of these AEDs is mainly due to the inhibition of sodium channel activity.

Antiepileptic drugs mechanisms of action carbamazepine oxcarbazepine BIA 2-093 BIA 2-024 


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  1. 1.
    Sindrup, S. H. and Jensen, T. S. 1999. Efficacy of pharmacological treatments of neuropathic pain: un update and effect related to mechanism of drug action. Pain 83:389–400.Google Scholar
  2. 2.
    Albani, F., Riva, R., and Baruzzi, A. 1995. Carbamazepine clinical pharmacology: a review. Pharmacopsychiat. 28:235–244.Google Scholar
  3. 3.
    Kerr, B. M. and Levy, R. H. 1989. Carbamazepine. Carbamazepine epoxide. Pages 505–520, in Levy, R., Mattson, R., Meldrum, B., Penry, J. K., and Dreifuss, F. E. (eds.), Antiepileptic drugs, Raven Press, New York.Google Scholar
  4. 4.
    Shorvon, S. D. 1996. The epidemiology and treatment of chronic and refractory epilepsy. Epilepsia 28:S64–S70.Google Scholar
  5. 5.
    Yasui, N., Otani, K., Kaneko, S., Shimoyama, R., Ohkubo, T., and Sugawara, K. 1997. Carbamazepine toxicity induced by clarithromycin coadministration in psychiatric patients. Int. Clin. Psychopharmacol. 12:225–229.Google Scholar
  6. 6.
    Emilien, G. and Maloteaux, J. M. 1988. Pharmacological management of epilepsy. Mechanism of action, pharmacokinetic drug interactions, and new drug discovery possibilities. Int. J. Clin. Pharmacol. Ther. 36:181–194.Google Scholar
  7. 7.
    Tateishi, T., Asoh, M., Nakura, H., Watanabe, M., Tanaka, M., Kumai, T., and Kobayashi, S. 1999. Carbamazepine induces multiple cytochrome P450 subfamilies in rats. Chem.-Biol. Int. 117:257–268.Google Scholar
  8. 8.
    Elger, C. E. and Bauer, J. 1998. New antiepileptic drugs in epileptology. Neuropsychobiology 38:145–148.Google Scholar
  9. 9.
    Loiseau, P. and Duché, P. 1995. Carbamazepine. Clinical use. Pages 555–566, in Levy, R. H., Mattson, R. H., and Meldrum, M. S. (eds.), Antiepileptic drugs, Raven Press, New York.Google Scholar
  10. 10.
    Rogawski, M. A. and Porter, R. J. 1990. Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol. Rev. 42:223–286.Google Scholar
  11. 11.
    Wolfe, J. F., Greenwood, T. D., and Mulheron, J. M. 1998. Recent trends in the development of new anti-epileptic drugs. Exp. Opin. Ther. Patents 8:361–381.Google Scholar
  12. 12.
    Benes, J., Parada, A., Figueiredo, A. A., Alves, P. C., Freitas, A. P., Learmonth, D. A., Cunha, R. A., Garrett, J., and Soaresda-Silva, P. 1999. Anticonvulsant and sodium channel-blocking properties of novel 10,11–dihydro-5H-dibenz[b, f ]azepine-5–carboxamide derivatives. J. Med. Chem. 42:2582–2587.Google Scholar
  13. 13.
    Benes, J., Soares-da-Silva, P., and Learmonth, D. 1999. Derivatives of 10,11–dihydro-10–oxo-5H-dibenz[b,f ]azepine-5–carboxamide. United States Patent. Patent Number 5,866,566.Google Scholar
  14. 14.
    McLean, M. J. and Macdonald, R. L. 1986. Carbamazepine and 10,11–epoxy-carbamazepine produce use-and voltage-dependent limitation of rapidly firing action potentials of mouse central neurons in cell culture. J. Pharmacol. Exp. Ther. 238:727–732.Google Scholar
  15. 15.
    Elliott, P. 1990. Action of antiepileptic and anaesthetic drugs on Na-and Ca-spikes in mammalian non-myelinated axons. Eur. J. Pharmacol. 175:155–163.Google Scholar
  16. 16.
    Macdonald, R. L. and Kelly, K. M. 1993. Antiepileptic drug mechanism of action. Epilepsia 34:S1–S8.Google Scholar
  17. 17.
    Willow, M., Gonoi, T., and Catterall, W. A. 1985. Voltage clamp analysis of the inhibitory action of diphenylhydantoin and carbamazepine on voltage-sensitive sodium channels in neuroblastoma cells. Mol. Pharmacol. 27:549–558.Google Scholar
  18. 18.
    Rush, A. M. and Elliott, J. R. 1997. Phenytoin and carbamazepine-Differential inhibition of sodium currents in small cells from adult rat dorsal root ganglia. Neurosci. Lett. 226:95–98.Google Scholar
  19. 19.
    Courtney, K. R. and Etter, E. F. 1983. Modulated anticonvulsant block of sodium channels in nerve and muscle. Eur. J. Pharmacol. 88:1–9.Google Scholar
  20. 20.
    Kuo, C. C., Chen, R. S., Lu, L., and Chen, R. C. 1997. Carbamazepine inhibition of neuronal Na+ currents-quantitative distinction from phenytoin and possible therapeutic implications. Mol. Pharmacol. 51:1077–1083.Google Scholar
  21. 21.
    Willow, M. and Catteral, W. A. 1982. Inhibition of binding of [3H]batrachotoxinin A 20–α-benzoate to sodium channels by the anticonvulsant drugs diphenylhydantoin and carbamazepine. Mol. Pharmacol. 22:627–635.Google Scholar
  22. 22.
    Willow, M., Kuenzel, E. A., and Catterall, W. A. 1984. Inhibition of voltage-sensitive sodium channels in neuroblastoma cells and synaptosomes by the anticonvulsant drugs diphenylhydantoin and carbamazepine. Mol. Pharmacol. 25:228–234.Google Scholar
  23. 23.
    Taylor, C. P. 1996. Voltage-gated Na+ channels as targets for anticonvulsant, analgesic and neuroprotective drugs. Curr. Pharma. Design 2:375–388.Google Scholar
  24. 24.
    Walden, J., Grunze, H., Bingmann, D., Liu, Z., and Düsing, R. 1992. Calcium antagonistic effects of carbamazepine as a mechanism of action in neuropsychiatric disorders: studies in calcium dependent model epilepsies. Eur. Neuropsychopharmacol. 2:455–462.Google Scholar
  25. 25.
    Walden, J., Grunze, H., Mayer, A., DÚsing, R., Schirrmacher, K., Liu, Z., and Bingmann, D. 1993. Calcium-antagonistic effects of carbamazepine in epilepsies and affective psychosis. Neuropsychobiol. 27:171–175.Google Scholar
  26. 26.
    Schirrmacher, K., Mayer, A., Walden, J., Dusing, R., and Bingmann, D. 1993. Effects of carbamazepine on action potentials and calcium currents in rat spinal ganglion cells in vitro. Neuropsychobiol. 27:176–179.Google Scholar
  27. 27.
    Schirrmacher, K., Mayer, A., Walden, J., Dusing, R., and Bingmann, D. 1995. Effects of carbamazepine on membrane properties of rat sensory spinal ganglion cells in vitro. Eur. Neuropsychopharmacol. 5:501–507.Google Scholar
  28. 28.
    Yoshimura, R., Yanagihara, N., Terao, T., Minami, K., Abe, K., and Izumi, F. 1998. Inhibition by carbamazepine of various ion channel-mediated catecholamine secretion in cultured bovine adrenal medullary cells. Naunyn Schmiedeberg's Arch. Pharmacol. 352:297–303.Google Scholar
  29. 29.
    Yoshimura, R., Yanagihara, N., Terao, T., Minami, K., Toyohira, Y., Ueno, S., Uezono, Y., Abe, K., and Izumi, F. 1998. An active metabolite of carbamazepine, carbamazepine-10,11–epoxide, inhibits ion channel-mediated catecholamine secretion in cultured bovine adrenal medullary cells. Psychopharmacol. 135:368–373.Google Scholar
  30. 30.
    Schumacher, T. B., Beck, H., Steinhäuser, C., Schramm, J., and Elger, C. E. 1998. Effects of phenytoin, carbamazepine, and gabapentin on calcium channels in hippocampal granule cells from patients with temporal lobe epilepsy. Epilepsia 39:355–363.Google Scholar
  31. 31.
    Ambrósio, A. F., Silva, A. P., Malva, J. O., Soares-da-Silva, P., Carvalho, A. P., and Carvalho, C. M. 1999. Carbamazepine inhibits L-type Ca2+ channels in cultured rat hippocampal neurons stimulated with glutamate receptor agonists. Neuropharmacology 38:1349–1359.Google Scholar
  32. 32.
    Zona, C., Tancredi, V., Palma, E., Pirrone, G. C., and Avoli, M. 1990. Potassium currents in rat cortical neurons in culture are enhanced by the antiepileptic drug carbamazepine. Can. J. Physiol. Pharmacol. 68:545–547.Google Scholar
  33. 33.
    Sayer, R. J., Brown, A. M., Schwindt, P. C., and Crill, W. E. 1993. Calcium currents in acutely isolated human neocortical neurons. J. Neurophysiol. 69:1596–1606.Google Scholar
  34. 34.
    Kito, M., Machara, M., and Watanabe, K. 1994. Antiepileptic drugs-calcium current interaction in cultured human neuroblastoma cells. Seizure 3:141–149.Google Scholar
  35. 35.
    Ambrósio, A. F., Silva, A. P., Malva, J. O., Soares-da-Silva, P., Carvalho, A. P., and Carvalho, C. M. 2001. Inhibition of glutamate release by BIA 2–093 and BIA 2–024, two novel derivatives of carbamazepine, due to blockade of sodium but not calcium channels. Biochem. Pharmacol. 61:1271–1275.Google Scholar
  36. 36.
    Olpe, H., Kolb, C. N., Hausdorf, A., and Haas, H. L. 1991. 4–aminopyridine and barium chloride attenuate the antiepileptic effect of carbamazepine in hippocampal slices. Experientia 47:254–257.Google Scholar
  37. 37.
    Matsumoto, Y., Enomoto, K., Moritake, K., and Maeno, T. 1998. Effects of carbamazepine on nerve activity and transmitter release in neuroblastoma-glioma hybrid cells and the frog neuromuscular junction. Cell Biol. Toxicol. 14:191–198.Google Scholar
  38. 38.
    Dreixler, J. C., Bian, J., Cao, Y., Roberts, M. T., Roizen, J. D., and Houamed, K. M. 2000. Block of rat brain recombinant SK channels by tricyclic antidepressants and related compounds. Eur. J. Pharmacol. 401:1–7.Google Scholar
  39. 39.
    Wooltorton, J. R. A. and Mathie, A. 1993. Block of potassium currents in rat isolated sympathetic neurones by tricyclic antidepressants and structurally related compounds. Br. J. Pharmacol. 110:1126–1132.Google Scholar
  40. 40.
    Lee, K., McKenna, F., Rowe, I. C., and Ashford, M. L. 1997. The effects of neuroleptic and tricyclic compounds on BKCa channel activity in rat isolated cortical neurones. Br. J. Pharmacol. 121:1810–1816.Google Scholar
  41. 41.
    Rundfeldt, C. 1997. The new anticonvulsant retigabine (D-23129) acts as an opener of K+ channels in neuronal cells. Eur. J. Pharmacol. 336:243–249.Google Scholar
  42. 42.
    Gasser, T., Reddington, M., and Schubert, P. 1988. Effect of carbamazepine on stimulus-evoked Ca2+ fluxes in rat hippocampal slices and its interaction with A1-adenosine receptors. Neurosci. Lett. 91:189–193.Google Scholar
  43. 43.
    Weir, R. L., Anderson, S. M., and Daly, J. W. 1990. Inhibition of N6-[3H]cyclohexyladenosine binding by carbamazepine. Epilepsia 31:503–512.Google Scholar
  44. 44.
    Van Calker, D., Steber, R., Klotz, K. N., and Greil, W. 1991. Carbamazepine distinguishes between adenosine receptors that mediate different second messenger responses. Eur. J. Pharmacol. 206:285–290.Google Scholar
  45. 45.
    Biber, K., Fiebich, B. L., Gebicke-Harter, P., and Van Calker, D. 1999. Carbamazepine-induced upregulation of adenosine A1-receptors in astrocyte cultures affects coupling to the phosphoinositol signaling pathway. Neuropsychopharmacology 20:271–278.Google Scholar
  46. 46.
    Daval, J. L., Deckert, J., Weiss, S. R., Post, R. M., and Marangos, P. J. 1989. Upregulation of adenosine A1 receptors and forskolin binding sites following chronic treatment with caffeine or carbamazepine: a quantitative autoradiographic study. Epilepsia 30:26–33.Google Scholar
  47. 47.
    Skerrit, J. H., Davies, L. P., and Johnston, G. A. (1983) Interactions of the anticonvulsant carbamazepine with adenosine receptors. 1. Neurochemical studies. Epilepsia 24:634–642.Google Scholar
  48. 48.
    Okada, M., Hirano, T., Mizuno, K., Chiba, T., Kawata, Y., Kiryu, K., Wada, K., Tasaki, H., and Kaneko, S. 1997. Biphasic effects of carbamazepine on the dopaminergic system in rat striatum and hippocampus. Epilepsy Res. 28:143–153.Google Scholar
  49. 49.
    Larkin, J. G., Thompson, G. G., Scobie, G., Drennan, J. E., and Brodie, M. J. 1991. Lack of major effects on mouse brain adenosine A1 receptors of oral carbamazepine and calcium antagonists. Epilepsia 32:729–734.Google Scholar
  50. 50.
    Malhotra, J. and Gupta, Y. K. 1999. Effect of adenosinergic modulation on the anticonvulsant effect of phenobarbitone and carbamazepine. Methods Find. Exp. Clin. Pharmacol. 21:79–83.Google Scholar
  51. 51.
    Yan, Q. S., Mishra, P. K., Burger, R. L., Bettendorf, A. F., Jobe, P. C., and Dailey, J. W. 1992. Evidence that carbamazepine and antiepilepsirine may produce a component of their anticonvulsant effects by activating serotonergic neurons in genetically epilepsy-prone rats. J. Pharmacol. Exp. Ther. 261:652–659.Google Scholar
  52. 52.
    Dailey, J. W., Reith, M. E. A., Yan, Q. S., Li, M. Y., and Jobe, P. C. 1997. Carbamazepine increases extracellular serotonin concentration-Lack of antagonism by tetrodotoxin or zero Ca2+ Eur. J. Pharmacol. 328:153–162.Google Scholar
  53. 53.
    Dailey, J. W., R eith, M. E. A., Yan, Q. S., Li, M. Y., and Jobe, P. C. 1997. Anticonvulsant doses of carbamazepine increase hippocampal extracellular serotonin in genetically epilepsyprone rats-Dose response relationships. Neurosci. Lett. 227:13–16.Google Scholar
  54. 54.
    Dailey, J. W., Reith, M. E. A., Steidley, K. R., Milbrandt, J. C., and Jobe, P. C. 1998. Carbamazepine-induced release of serotonin from rat hippocampus in vitro. Epilepsia 39:1054–1063.Google Scholar
  55. 55.
    Okada, M., Kawata, Y., Mizuno, K., Wada, K., Kondo, T., and Kaneko, S. 1998. Interaction between Ca2+ K+ carbamazepine and zonizamide on hippocampal extracellular glutamate monitored with a microdialysis electrode. Brit. J. Pharmacol. 124:1277–1285.Google Scholar
  56. 56.
    Southam, E., Kirkby, D., Higgins, G. A., and Hagan, R. M. 1998. Lamotrigine inhibits monoamine uptake in vitro and modulates 5–hydroxytryptamine uptake in rats. Eur. J. Pharmacol. 358:19–24.Google Scholar
  57. 57.
    Pranzatelli, M. R. 1988. Effect of antiepileptic and antimyoclonic drugs on serotonin receptors in vitro. Epilepsia 29:412–419.Google Scholar
  58. 58.
    Elphick, M. 1989. Effects of carbamazepine on dopamine function in rodents. Psychopharmacology 99:532–536.Google Scholar
  59. 59.
    Kowalik, S., Levitt, M., and Barkai, A. I. 1984. Effects of carbamazepine and anti-depressant drugs on endogenous catecholamine levels in the cerebroventricular compartment of the rat. Psychopharmacology 83:169–171.Google Scholar
  60. 60.
    Barros, H. M., Braz, S., and Leite, J. R. 1986. Effect of carbamazepine on dopamine release and reuptake in rat striatal slices. Epilepsia 27:534–537.Google Scholar
  61. 61.
    Baf, M. H., Subhash, M. N., Lakshmana, K. M., and Rao, B. S. 1994. Alterations in monoamine levels in discrete regions of rat brain after chronic administration of carbamazepine. Neurochem. Res. 19:1139–1143.Google Scholar
  62. 62.
    Ichikawa, J. and Meltzer, H. Y. 1999. Valproate and carbamazepine increase prefrontal dopamine release by 5–HT1A receptor activation. Eur. J. Pharmacol. 380:R1–R3.Google Scholar
  63. 63.
    Post, R. M., Rubinow, D. R., Uhde, T. W., Ballenger, J. C., and Linnoila, M. 1986. Dopaminergic effects of carbamazepine. Relationship to clinical response in affective illness. Arch. Gen. Psychiatry 43:392–396.Google Scholar
  64. 64.
    Rogawski, M. A. 1995. Excitatory amino acids and seizures. Pages 219–237, in Stone, T. W. (eds.), CNS neurotransmitters and neuromodulators-Glutamate, CRC Press, London.Google Scholar
  65. 65.
    Olpe, H.-R., Baudry, M., and Jones, R. S. G. 1985. Electrophysiological and neurochemical investigations on the action of carbamazepine on the rat hippocampus. Eur. J. Pharmacol. 110:71–80.Google Scholar
  66. 66.
    Crowder, J. M. and Bradford, H. F. 1987. Common anticonvulsants inhibit Ca2+ uptake and amino acid neurotransmitter release in vitro. Epilepsia 28:378–382.Google Scholar
  67. 67.
    Waldmeier, P. C., Baumann, P. A., Wicki, P., Feldtrauer, J. J., Stierlin, C., and Schmutz, M. 1995. Similar potency of carbamazepine, oxcarbazepine, and lamotrigine in inhibiting the release of glutamate and other neurotransmitters. Neurology 45:1907–1913.Google Scholar
  68. 68.
    Waldmeier, P. C., Martin, P., Stocklin, K., Portet, C., and Schmutz, M. 1996. 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. 354:164–172.Google Scholar
  69. 69.
    Lingamaneni, R. and Hemmings Jr., H. C. 1999. Effects of anticonvulsants on veratridine-and KCl-evoked glutamate release from rat cortical synaptosomes. Neurosci. Lett. 276:127–130.Google Scholar
  70. 70.
    Lampe, H. and Bigalpe, H. 1990. Carbamazepine blocks NMDA-activated currents in cultured spinal cord neurons. Neuroreport 1:26–28.Google Scholar
  71. 71.
    Cai, Z. and McCaslin, P. P. 1992. Amitriptyline, desipramine, cyproheptadine and carbamazepine, in concentrations used therapeutically, reduce kainate-and N-methyl-D-aspartateinduced intracellular Ca2+ levels in neuronal culture. Eur. J. Pharmacol. 219:53–57.Google Scholar
  72. 72.
    Lancaster, J. M. and Davies, J. A. 1992. Carbamazepine inhibits NMDA-induced depolarization in cortical wedges prepared from DBA/2 mice. Experientia 48:751–753.Google Scholar
  73. 73.
    Sofia, R. D., Gordon, R., Gels, M., and Diamantis, W. 1994. Comparative effects of felbamate and other compounds on N-methyl-D-aspartic acid-induced convulsions and lethality in mice. Pharmacol. Res. 29:139–144.Google Scholar
  74. 74.
    Hough, C. J., Irwin, R. P., Gao, X.-M., Rogawski, M. A., and Chuang, D.-M. 1996. Carbamazepine inhibition of N-methyl-D-aspartate-evoked calcium influx in rat cerebellar granule cells. J. Pharmacol. Exp. Ther. 276:143–149.Google Scholar
  75. 75.
    Phillips, L., Martin, K. F., Thompson, K. S. J., and Heal, D. J. 1997. Weak blockade of AMPA receptor-mediated depolarizations in the rat cortical wedge by phenytoin but not lamotrigine or carbamazepine. Eur. J. Pharmacol. 337:189–195.Google Scholar
  76. 76.
    Grant, K. A., Snell, L. D., Rogawski, M. A., Thurkauf, A., and Tabakoff, B. 1992. Comparison of the effects of the uncompetitive N-methyl-D-aspartate antagonist (6)-5–aminocarbonyl-10,11–dihydro-5H-dibenzo [a,d ] cyclohepten-5,10–imine (ADCI) with its structural analogue dizocilpine (MK-801) and carbamazepine on ethanol withdrawal seizures. J. Pharmacol. Exp. Ther. 260:1017–1022.Google Scholar
  77. 77.
    Ambrósio, A. F., Silva, A. P., AraÚjo, I., Malva, J. O., Soaresda-Silva, P., Carvalho, A. P., and Carvalho, C. M. 2000. Neurotoxic/ neuroprotective profile of carbamazepine and two new putative antiepileptic drugs, BIA 2–093 and BIA 2–024. Eur. J. Pharmacol. 406:191–201.Google Scholar
  78. 78.
    Marangos, P. J., Post, R. M., Patel, J., Zander, K., Parma, A., and Weiss, S. 1983. Specific and potent interactions of carbamazepine with brain adenosine receptors. Eur. J. Pharmacol. 93:175–182.Google Scholar
  79. 79.
    Bender, A. S. and Hertz, L. 1985. Binding of [3H]Ro 5–4864 in primary cultures of astrocytes. Brain Res. 341:41–49.Google Scholar
  80. 80.
    Weiss, S. R., Post, R. M., Patel, J., and Marangos, P. J. 1985. Differential mediation of the anticonvulsant effects of carbamazepine and diazepam. Life Sci. 36:2413–2419.Google Scholar
  81. 81.
    Weizman, A., Tanne, Z., Karp, L., Martfield, Y., Tyano, S., and Gavish, M. 1987. Carbamazepine up-regulates the binding of [3H]PK 11195 to platelets of epileptic patients. Eur. J. Pharmacol. 141:471–474.Google Scholar
  82. 82.
    Ferrarese, C., Marzorati, C., Perego, M., Bianchi, G., Cavarretta, R., Pierpa, C., Moretti, G., and Frattola, L. 1995. Effect of anticonvulsant drugs on peripheral benzodiazepine receptors of human lymphocytes. Neuropharmacology 34:427–431.Google Scholar
  83. 83.
    Ludvig, N., Mishra, P. K., and Jobe, P. C. Dibutyryl cyclic AMP has epileptogenic potential in the hippocampus of freely behaving rats: a combined EEG-intracerebral microdialysis study. Neurosci. Lett. 141:187–191.Google Scholar
  84. 84.
    Hudson, C. J., Young, L. T., Li, P. P., and Warsh, J. J. 1993. CNS signal transduction in the pathophysiology and pharmacotherapy of affective disorders and schizophrenia. Synapse 13:278–293.Google Scholar
  85. 85.
    Myllyla, V. V. 1976. Effect of convulsions and anticonvulsive drugs on cerebrospinal fluid cyclic AMP in rabbits. Eur. Neurol. 14:97–107.Google Scholar
  86. 86.
    Palmer, G. C., Jones, D. J., Medina, M. A., and Stavinoha, W. B. 1979. Anticonvulsant drug actions on in vitro and in vivo levels of cyclic AMP in the mouse brain. Epilepsia 20: 95–104.Google Scholar
  87. 87.
    Lewin, E., and Bleck, V. 1977. Cyclic AMP accumulation in cerebral cortical slices: effect of carbamazepine, phenobarbital, and phenytoin. Epilepsia 18:237–242.Google Scholar
  88. 88.
    Ferrendelli, J. A. and Kinscherf, D. A. 1979. Inhibitory effects of anticonvulsant drugs on cyclic nucleotides accumulation in the brain. Ann. Neurol. 5:533–538.Google Scholar
  89. 89.
    Elphick, M., Taghavi, Z., Powell, T., and Godfrey, P. P. 1990. Chronic carbamazepine down-regulates adenosine A2 receptors: studies with the putative selective adenosine antagonists PD115,199 and PD116,948. Psychopharmacology 100:522–529.Google Scholar
  90. 90.
    Palmer, G. C., Jones, D. J., Medina, M. A., and Stavinoha, W. B. 1979. Anticonvulsant drug actions on in vitro levels of cyclic AMP in the mouse brain. Epilepsia 20:95–104.Google Scholar
  91. 91.
    Post, R. M., Ballenger, J. C., Uhde, T. W., Smith, C., Rubinow, D. R., and Bunney, W. R. Jr 1982. Effect of carba-mazepine on cyclic nucleotides in CSF of patients with affective ilness. Biol. Psychiatry 17:1037–1045.Google Scholar
  92. 92.
    Chen, G., Pan, B. S., Hawver, D. B., Wright, C. B., and Potter, W. Z. 1996. Attenuation of cyclic-AMP production by carbamazepine. J. Neurochem. 67:2079–2086.Google Scholar
  93. 93.
    Afanas'ev, I., Kudrin, V., Rayevsky, K. S., Varga, V., Saransaari, P., and Oja, S. S. 1999. Lamotrigine and carbamazepine affect differently the release of D-[3H]aspartate from mouse cerebral cortex slices: involvement of NO. Neurochem. Res. 24:1153–1159.Google Scholar
  94. 94.
    Wamil, A. W., Portet, C., Jensen, P. K., Schmutz, M., and McLean, M. J. 1991. Oxcarbazepine and its monohydroxy metabolite limit action potential firing by mouse central neurons in culture. Epilepsia 32:65–66.Google Scholar
  95. 95.
    McLean, M. J., Schmutz, M., Wamil, A. W., Olpe, H. R., Portet, C., and Fedmann, K. F. 1994. Oxcarbazepine: mechanisms of action. Epilepsia, 35:S55–S59.Google Scholar
  96. 96.
    Wamil, A. W., Schmutz, M., Portet, C., Feldmann, K. F., and McLean, M. J. 1994. Effects of oxcarbazepine and 10–hydroxycarbazepine on action potential firing and generalized seizures. Eur. J. Pharmacol. 271:301–308.Google Scholar
  97. 97.
    Schmutz, M., Brugger, F., Gentsch, C., McLean, M. J., and Olpe, H. R. 1994. Oxcarbazepine: preclinical anticonvulsant profile and putative mechanisms of action. Epilepsia 35:S47–S50.Google Scholar
  98. 98.
    Stefani, A., Pisani, A., De Murtas, M., Mercuri, N. B., Marciani, M. G., and Calabresi, P. 1995. Action of GP 47779, the active metabolite of oxcarbazepine, on the corticostriatal system. II. Modulation of high-voltage-activated calcium currents. Epilepsia 336:997–1002.Google Scholar
  99. 99.
    Deckert, J., Berger, W., Kleopa, K., Heckers, S., Ransmayr, G., Heisen, H., Beckmann, H., and Riederer, P. 1993. Adenosine A1 receptors in human hippocampus: inhibition of [3H]8–cyclopentyl-1,3–dipropylxanthine binding by antagonistic drugs. Neurosci. Lett. 150:191–194.Google Scholar
  100. 100.
    Fujiwara, Y., Sato, M., and Otsuki, S. 1986. Interaction of carbamazepine and other drugs with adenosine (A1 and A2) receptors. Psychopharmacology 90:332–335.Google Scholar
  101. 101.
    Joca, S. R., Skalisz, L. L., Beijamini, V., Vital, M. A., and Andreatini, R. 2000. The antidepressive-like effect of oxcarbazepine: possible role on dopaminergic neurotransmission. Eur. Neuropsychopharmacol. 10:223–228.Google Scholar
  102. 102.
    Ambrósio, A. F. 2000. Mechanisms of action of antiepileptic drugs and neurotoxicity in hippocampus. PhD Thesis.Google Scholar
  103. 103.
    Learmonth, D. A., Benes, J., Parada, A., Hainzl, D., Beliaev, A., Bonifácio, M. J., Matias, P. M., Carrondo, M. A., Garrett, J. and Soares-da-Silva, P. 2001. Synthesis, anticonvulsant properties and pharmacokinetic profile of novel 10,11–dihydro-10–oxo-5H-dibenz/b,f/azepine-5–carboxamide derivatives. Eur. J. Med. Chem. 36:227–236.Google Scholar
  104. 104.
    Hainzl, D., Parada, A., Soares-da-Silva, P. 2001. Metabolism of two new antiepileptic drugs and their principal metabolites S(1)-and R(2)-10,11–dihydro-10–hydroxy carbamazepine. Epilepsy Res. 44:197–206.Google Scholar
  105. 105.
    Bonifácio, M. J. and Soares-da-Silva, P. 2000. Effects of BIA 2–059 and BIA 2–093 on rat brain voltage-dependent sodium channels. Eur. J. Neurosci. 12 (Suppl. 11):11.20, p158.Google Scholar
  106. 106.
    Bonifácio, M. J., Sheridan, R. D., Parada, A., Cunha, R. A., Patmore, L., Soares-da-Silva, P. 2001. Interaction of the novel anticonvulsant, BIA 2–093, with voltage-gated sodium channels: comparison with carbamazepine. Epilepsia 42:600–608.Google Scholar
  107. 107.
    Parada, A. and Soares-da-Silva, P. 2000. Effects of BIA 2–093, carbamazepine and oxcarbazepine on transmitter release: an in vitro study. Eur. J. Neurosci. 12 (Suppl. 11):16.15, p250.Google Scholar
  108. 108.
    Borges, N., Parada, A., and Soares-da-Silva, P. 2000. Effects of BIA 2–093, carbamazepine and oxcarbazepine on transmitter release: a microdialysis study. Eur. J. Neurosci. 12 (Suppl. 11):16.20, p255.Google Scholar

Copyright information

© Plenum Publishing Corporation 2002

Authors and Affiliations

  • António F. Ambrósio
    • 1
  • Patrício Soares-da-Silva
    • 2
  • Caetana M. Carvalho
    • 1
  • Arsélio P. Carvalho
    • 1
  1. 1.Department of Cell Biology, Center for Neuroscience of Coimbra, Department of ZoologyUniversity of CoimbraCoimbra
  2. 2.Department of Research & Development, BialS. Mamede do CoronadoPortugal

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