Abstract
Epilepsy, a functional disturbance of the CNS and induced by abnormal electrical discharges, manifests by recurrent seizures. Although new antiepileptic drugs have been developed during recent years, still more than one third of patients with epilepsy are refractory to treatment. Therefore, the search for new mechanisms that can regulate cellular excitability are of utmost importance. Three currently available drugs are of special interest because they have novel mechanisms of action and are especially effective for partial onset seizures. Vigabatrin is a selective and irreversible GABA-transaminase inhibitor that greatly increases whole-brain levels of GABA. Tiagabine is a potent inhibitor of GABA uptake into neurons and glial cells. Topiramate is considered to produce its antiepileptic effect through several mechanisms, including modification of Na+ -and/or Ca2+-dependent action potentials, enhancement of GABA-mediated Cl− fluxes into neurons, and inhibition of kainate-mediated conductance at glutamate receptors of the AMPA/kainate type. This review will discuss these mechanisms of action at the cellular and molecular levels.
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REFERENCES
Stefan, H., Halasz P., Gil-Nagel, A., Shorvon, S., Bauer, G., Ben Menachem, E., Perucca, E., Wieser, H. G., and Steinlein, O. 2001. Recent advances in the diagnosis and treatment of epilepsy. Eur. J. Neurol. 8:519–539.
Kwan, P. and Brodie, M. J. 2000. Early identification of refractory epilepsy. N. Engl. J. Med. 342:314–319.
Schwartz, R. D. 1988. The GABAA receptor-gated ion channel: Biochemical and pharmacological studies of structure and function. Biochem. Pharmacol. 37:3369–3375.
Salt, T. E., Eaton, S. A., and Turner, J. P. 1996. Characterization of the metabotropic glutamate receptors (mGluRs) which modulate GABA-mediated inhibition in the ventrobasal thalamus. Neurochem. Int. 29:317–322.
Hamberger, A. and van Gelder, N. M. 1993. Metabolic manipulation of neuronal tissue to counter the hypersynchronous excitation of migraine and epilepsy. Neurochem. Res. 18:503–509.
Greengard, P. 2001. The neurobiology of slow synaptic transmission. Science 294:1024–1030.
Traub, R. D., Jefferys, J. G., and Whittington, M. A. 1999. Functionally relevant and functionally disruptive (epileptic) synchronized oscillations in brain slices. Adv. Neurol. 79:709–724.
Ben-Ari, Y. and Cossart, R. 2000. Kainate, a double agent that generates seizures: Two decades of progress. Trends Neurosci. 23:580–587.
Lee, M C., Rho, J. L., Kim, M. K., Woo, Y. J., Kim, J. H., Nam, S. C., Suh, J. J., Chung, W. K., Moon, J. D., and Kim, H. I. 2001. c-JUN expression and apoptotic cell death in kainate-induced temporal lobe epilepsy. J. Korean Med. Sci. 16:649–656.
Frantseva, M. V., Velazquez, J. L., Hwang, P. A., and Carlen, P. L. 2000. Free radical production correlates with cell death in an in vitro model of epilepsy. Eur. J. Neurosci. 12:1431–1439.
Sattler, R. and Tymianski, M. 2000. Molecular mechanisms of calcium-dependent excitotoxicity. J. Mol. Med. 78:3–13.
Mattson, M. P., Keller, J. N., and Begley, J. G. 1998. Evidence for synaptic apoptosis. Exp. Neurol. 153:35–48.
Sonnewald, U., Westergaard, N., and Schousboe, A. 1997. Glutamate transport and metabolism in astrocytes. Glia 21:56–63.
Reiter, R. J., Acuna-Castroviejo, D., Tan, D. X., and Burkhardt, S. 2001. Free radical-mediated molecular damage: Mechanisms for the protective actions of melatonin in the central nervous system. Ann. N. Y. Acad. Sci. 939:200–215.
Novelli, A., Reilly, J. A., Lysko, P. G., and Henneberry, R. C. 1988. Glutamate becomes neurotoxic via the N-methyl-D-aspartate receptor when intracellular energy levels are reduced. Brain Res. 451:205–212.
Sanchez-Carbente, M. R. and Massieu L. 1999. Transient inhibition of glutamate uptake in vivo induces neurodegeneration when energy metabolism is impaired. J. Neurochem. 72:129–138.
Dugan, L. L., Sensi, S. L., Canzoniero, L. M., Handran, S. D., Rothman, S. M., Lin, T. S., Goldberg, M. P., and Choi, D. W. 1995. Mitochondrial production of reactive oxygen species in cortical neurons following exposure to N-methyl-D-aspartate. J. Neurosci. 15:6377–6388.
Reynolds, I. J. and Hastings, T. G. 1995. Glutamate induces the production of reactive oxygen species in cultured forebrain neurons following NMDA receptor activation. J. Neurosci. 15:3318–3327.
Perez Velazquez, J. L., Frantseva, M. V., and Carlen, P. L. 1997. In vitro ischemia promotes glutamate-mediated free radical generation and intracellular calcium accumulation in hippocampal pyramidal neurons. J. Neurosci. 17:9085–9094.
Butcher, S. P., Jacobson, I., and Hamberger, A. 1988. On the epileptogenic effects of kainic acid and dihydrokainic acid in the dentate gyrus of the rat. Neuropharmacology 27:375–381.
Elliot, K. A. C. and van Gelder, N. M. 1958. Occlusion and metabolism of gamma aminobutyric acid by brain tissue. J. Neurochem. 3:28–40.
Jung, M. F., Lippert, B., Metcalf, B. W., Bohlen, P., and Schechter, P. J. 1977. Gamma-vinyl GABA (4–amino-hex-5–enoic acid), a new selective irreversible inhibitor of GABA-T: Effects on brain GABA metabolism in mice. J. Neurochem. 29:797–802.
Gale, K. 1986. Role of the substantia nigra in GABA-mediated anticonvulsant actions. In: Delgado-Escueta, A. V., Ward, A. A., Woodbury, D. M., and Porter, R. J. (eds.). Basic Mechanisms of the Epilepsies: Molecular and Cellular Approaches. 44:343–364. Advances in Neurology.
Schechter, P. J., Tranier, Y., and Grove, J. 1979. Attempts to correlate alterations in brain GABA metabolism by GABA-T inhibitors with their anticonvulsant effects. Pages 43–57, in Mandel, P., DeFeudes, E. V. (eds.). GABA-Biochemistry and CNS Functions. New York, Plenum Press.
Schechter, P. J., Tranier, Y., Jung, M. J., and Bohlen, P. 1977. Audiogenic seizure protection by elevated brain GABA concentration in mice: effects of gamma-acetylenic gaba and gammavinyl GABA, two irreversible GABA-T inhibitors. Eur. J. Pharmacol. 45:319–328.
Meldrum, B. S. and Horton, R. 1978. 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 59:47–50.
Grove, J., Schechter, P. J., Tell, G., Koch-Weser, J., Sjoerdsma, A., Warter, J. M., Marescaux, C., and Rumbach, L. Increased gamma-aminobutyric acid (GABA), homocarnosin and beta-ala-nine in cerebrospinal fluid of patients treated with gamma-vinyl GABA (4–amino-hex-5–enoic acid). Life Sci. 28:2431–2439.
Schechter, P. J., Hanke, N. F. J., Grove J., Huebert, N., and Sjoerdsma, A. 1984. Biochemical and clinical effects of gamma-vinyl GABA in patients with epilepsy. Neurology 134:34–39.
Pitkänen, A., Halonen, T., Ylinen, A., and Riekkinen, P. 1987. Somatostatin, β-endorphin, and prolactin levels in human cerebrospinal fluid during the gamma-vinyl GABA treatment of patients with complex partial seizures. Neuropeptides 9:185–195.
Sivenius, M. R. J., Ylinen, A., Murros, K., Matilainen, R., and Riekkinen, P. 1987. Double blind dose-reduction study of vigabatrin in complex partial epilepsy. Epilepsia 28:688–692.
Ben-Menachem, E., Persson, L. I., and Mumford, J. P. 1991. Effect of long term vigabatrin therapy on selected CSF neurotransmitter concentrations. J. Child. Neurology 6 (Suppl 2):11–16.
Ben-Menachem, E., Persson, L., Schechter, P. J., Haegele, K. D., Huebert, N.,Hardenberg, J., Dahlgren, L., and Mumford, J. P. 1988. Effects of single doses of vigabatrin on CSF concentrations of GABA, homocarnosine, homovanillic acid and 5–hydroxyindoleacedic acid in patients with complex partial seizures. Epilepsy Res. 2:96–101.
Ben-Menachem, E., Mumford, J., and Hamberger, A. 1993. Effect of long-term vigabatrin therapy on GABA and other amino acid concentrations in the central nervous system: A case study. Epilepsy Res. 16:241–243.
Ben-Menachem, E., Persson, L. I., Schechter, P. J., Haegele, K. D., Huebert, N., Hardenberg, J., Dahlgren, L., and Mumford, J. P. 1989. The effect of different vigabatrin treatment regimens on CSF biochemistry and seizure control in epileptic patients. Br. J. Clin. Pharmac. 27:79S-85S.
Kälviäinen, R., Halonen, T., Pitkänen, A., and Riekkinen, P. J. 1993. Amino acid levels in the cerebrospinal fluid of newly diagnosed epileptic patients: Effect of vigabatrin and carbamazepine monotherapy. J. Neurochem. 60:1244–1250.
Petroff, O. A. C., Rothman, D. L., Behar, K. L., and Mattson, R. H. 1995. Initial observations of effect of vigabatrin on in vivo 1H spectroscopic measurements of γ-aminobutyric acid, glutamate, and glutamine in human brain. Epilepsia 36:457–464.
Spanaki, M. V., Siegel, H., Kopylev, L., Fazilat, S., Dean, A., Liow, K., Ben-Menachem, E., Gaillard, W. D., and Theodore, W. H. 1999. The effect of vigabatrin (gamma-vinyl GABA) on cerebral blood flow and metabolism. Neurology 53:1518–1522.
Richens, A. 1991. Pharmacology and clinical pharmacology of vigabatrin. J. Child. Neurology 6:2S7–2S10.
Dalby, N. O. 2000. GABA-level increasing and anticonvulsant effects of three different GABA uptake inhibitors. Neuropharmacology 39:2399–2407.
Sills, G. J., Patsalos, P. N., Butler, E., Forrest, G., Ratnaraj, N., and Brodie, M. J. 2001. Visual field constriction: Accumulation of vigabatrin but not tiagabine in the retina. Neurology 57:196–200.
Kalviainen, R. 2001. Long-term safety of tiagabine. Epilepsia 42 (Suppl 3):46–48.
Marson, A. G., Kadir, Z. A., Hutton, J. L., and Chadwick, D. W. 1997. The new antiepileptic drugs: A systematic review of their efficacy and tolerability. Epilepsia 38:859–880.
Shank, R. P., Gardocki, J. F., Vaught, J. L., Davis, C. B., Schupsky, J. J., Raffa, R. B., Dodgson, S. J., Nortey, S. O., and Maryanoff, B. E. 1994. Topiramate: preclinical evaluation of structurally novel anticonvulsant. Epilepsia 35:450–460.
Montouris, G. D., Biton, V., and Rosenfeld, W. E. 2000. Non-focal generalized tonic-clonic seizures: response during long-term topiramate treatment. Topiramate YTC/YTCE Study Group. Epilepsia 41 (Suppl 1):S77–S81.
Sachdeo, R. C., Glauser, T. A., Ritter, F., Reife, R., Lim, P., and Pledger, G. 1999. A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome. Topiramate YL Study Group. Neurology 52:1882–1887.
Perucca, E. 2001. Clinical pharmacology and therapeutic use of the new antiepileptic drugs. Fundam Clin. Pharmacol. 15:405–417.
Zona, C., Ciotti, M. T., and Avoli, M. 1997. Topiramate attenuates voltage-gated sodium currents in rat cerebellar granule cells. Neurosci. Lett. 231:123–126.
White, H. S., Brown, S. D., Woodhead, J. H., Skeen, G. A., and Wolf, H. H. 1997. Topiramate enhances GABA-mediated chloride flux and GABA-evoked chloride currents in murine brain neurons and increases seizure threshold. Epilepsy Res. 28:167–179.
Gordey, M., DeLorey, T. M., and Olsen, R. W. 2000. Differential sensitivity of recombinant GABA(A) receptors expressed in Xenopus oocytes to modulation by topiramate. Epilepsia 41 (Suppl 1):S25–S29.
Gibbs, J. W. III., Sombati, S., DeLorenzo, R. J., and Coulter, D. A. 2000. Cellular actions of topiramate: Blockade of kainateevoked inward currents in cultured hippocampal neurons. Epilepsia 41 (Suppl 1):S10–S16.
Ängehagen, M., Shank, R., Hansson, E., Rönnbäck, L., and Ben-Menachem, E. 2001. Topiramate affects the ability of protein kinase to phosphorylate glutamate receptors activated by kainate. Epilepsia 42 (Suppl 7):S10.
Dodgson. S. J., Shank, R. P., and Maryanoff, B. E. 2000. Topiramate as an inhibitor of carbonic anhydrase isoenzymes. Epilepsia 41 (Suppl 1):S35–S39.
White, H. S. 1999. Comparative anticonvulsant and mechanistic profile of the established and newer antiepileptic drugs. Epilepsia 40 (Suppl 5):S2–S10.
Herrero, A. I., Del Olmo, N., Gonzales-Escalada, J. R. and Solis, J. M. 2002. Two new actions of topiramate: Inhibition of depolarizing GABA(A)-mediated responses and activation of a potassium conductance. Neuropharmacology 42:210–220.
Huang, R. D., Smith, M. F., and Zahler, W. L. 1982. Inhibition of forskolin-activated adenylate cyclase by ethanol and other solvents. J. Cyclic Nucleotide Res. 8:385–394.
Chijiwa, T., Mishima, A., Hagiwara, M., Sano, M., Hayashi, K., Inoue, T., Naito, K., Toshioka, T., and Hidaka, H. 1990. Inhibition of forskolin-induced neurite outgrowth and protein phosphorylation by a newly synthesized selective inhibitor of cyclic AMP-dependent protein kinase, N-[2–(p-bromocinnamylamino)ethyl]-5–isoquinolinesulfonamide (H-89), of PC12D pheochromocytoma cells. J. Biol. Chem. 265:5267–5272.
Raman, I. M., Tong, G., and Jahr, C. E. 1996. Beta-adrenergic regulation of synaptic NMDA receptors by cAMP-dependent protein kinase. Neuron 16:415–421.
Aker, R. G., Ozkara, C., Dervent, A., and Yilmaz Onat, F. 2002. Enhancement of spike and wave discharges by microinjection of bicuculline into the reticular nucleus of rats with absence epilepsy. Neurosci. Lett. 322:71–74.
Panayiotopoulos, C. P. 1999. Importance of specifying the type of epilepsy. Lancet 354:2002–2003.
Panayiotopoulos, C. P., Agathonikou, A., Sharoqi, I. A., and Parker, A. P. 1997. Vigabatrin aggravates absences and absence status. Neurology 149:1467.
Slaght, S. J., Leresche, N., Deniau, J. M., Crunelli, V., and Charpier, S. 2000. Activity of thalamic reticular neurons during spontaneous genetically determined spike and wave discharges. J. Neurosci. 22:2323–2334.
Knake, S., Hamer, H. M., Schomburg, U., Oertel, W. H., and Rosenow, F. 1999. Tiagabine-induced absence status in idiopathic generalized epilepsy. Seizure 8:314–317.
Andre, V., Ferrandon, A., Marescaux, C., Nehlig, A. 2001. Vigabatrin protects against hippocampal damage but is not antiepileptogenic in the lithium-pilocarpine model of temporal lobe epilepsy. Epilepsy Res. 47:99–117.
Yang, Y., Li, Q., and Shuaib, A. 2000. Enhanced neuroprotec-tion and reduced hemorrhagic incidence in focal cerebral ischemia of rat by low dose combination therapy of urokinase and topiramate. Neuropharmacology 39:881–888.
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Ängehagen, M., Ben-Menachem, E., Rönnbäck, L. et al. Novel Mechanisms of Action of Three Antiepileptic Drugs, Vigabatrin, Tiagabine, and Topiramate. Neurochem Res 28, 333–340 (2003). https://doi.org/10.1023/A:1022393604014
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DOI: https://doi.org/10.1023/A:1022393604014