• 1
    Krall RL., Penry JK., White BG., Kupferberg HJ., Swinyard EA. Krall RL, Penry, JK., White, BG., Kupferberg, HJ., Swinyard, EA. Antiepileptic drug development: II. Anticonvulsant drug screening. Epilepsia 1978; 19 40428.
  • 2
    Cereghino JJ., Kupferberg HJ. Preclinical testing. In: FrenchJA., DichterMA., LeppikIE. New antiepileptic drug development: preclinical and clinical aspects., Amsterdam : Elsevier, 1993; 1930.
  • 3
    Loscher W., Schmidt D. Strategies in antiepileptic drug development: is rational drug design superior to random screening and structural variation. Epilepsy Res 1994; 17 95134.
  • 4
    Rogawski MA. Epilepsy. In: PullanL., PatelJ. Neurotherapeutics: emerging strategies., Totowa , NJ : Humana Press, 1996; 193.
  • 5
    Meldrum BS. Current strategies for designing and identifying new antiepileptic drugs. In: EngelJ.Jr, PedleyTA. Epilepsy: a comprehensive textbook. Philadelphia : Lippincott-Raven Publishers 1997; 140516.
  • 6
    Ragsdale DS., Scheuer T., Catterall WA. Frequency and voltage dependent inhibition of type HA Na+ channels expressed in a mammalian cell line by local anaesthetic, antiarrhythmic and anticonvulsant drugs. Mol Pharmacol 1991; 40 75665.
  • 7
    Macdonald RL., Meldrum BS. Principles of antiepileptic drug action. In: LevyRH., MattsonRH., MeldrumBS. Antiepileptic drugs., 4th ed. New York : Raven Press, 1995; 6178.
  • 8
    Ragsdale DS., McPhee JC., Scheuer T., Catterall WA. Molecular determinants of state-dependent block of Na+ channels by local anaesthetics. Science 1994; 265 17248.
  • 9
    Taylor CP., Meldrum BS. Na+ channels as targets for neuroprotective drugs. Trends Pharmacol Sci 1995; 16 30916.
  • 10
    Balser JR., Nuss HB., Chaimvimonvat N., Perez-Garcia MT., Marban E., Tomaselli GF. External pore residue mediates slow inactivation in Ul rat skeletal muscle sodium channels. J Physiol 1996; 494 43142.
  • 11
    Randall A., Tsien RW. Pharmacological dissection of multiple types of Ca++ channel currents in rat cerebellar granule neurons. J Neurosci 1995; 15 29953012.
  • 12
    Caterall WA. Structure and function of voltage-gated ion channels. Annu Rev Biochem 1995; 64 493531.
  • 13
    Hofmann F., Biel M., Flockerzi V. Molecular basis for Ca++ channel diversity. Annu Rev Neurosci 1994; 17 399418.
  • 14
    Caterall WA. Cellular and molecular biology of voltage-gated sodium channels. Physiol Rev 1992; 72 1548.
  • 15
    Cousin MA., Nicholls DG., Pocock JM. Flunarizine inhibits both calcium-dependent and -independent release of glutamate from synaptosomes and cultured neurones. Brain Res 1993; 606 22736.
  • 16
    Lingenhohl K., Small DL., Monette R., et al. Exploration of P-type Ca2+ channels as drug targets for the treatment of epilepsy or ischemic stroke. Neuropharmacology 1997; 36.
  • 17
    Sah P. Ca2+-activated K+ currents in neurones: types, physiological roles and modulation. Trends Neurol Sci 1996; 19 1504.
  • 18
    Gandolfo G., Romettino S., Gottesman C., et al. K+ channel openers decrease seizures in genetically epileptic rats. Eur J Pharmacol 1989; 167 1813.
  • 19
    Weston AH., Edwards G. Recent progress in potassium channel opener pharmacology. Biochem Pharmacol 1992; 43 4754.
  • 20
    Beck H., Blumke I., Kral T., et al. Properties of a delayed rectifier potassium current in dentate granule cells isolated from the hippocampus of patients with chronic temporal lobe epilepsy. Epilepsia 1996; 37 892901.
  • 21
    Janigro D., Gasparini S., D'Ambrosio R., McKhann G., DiFrancesco D. Reduction of K+ uptake in glia prevents long-term depression maintenance and causes epileptiform activity. J Neurosci 1997; 17 281324.
  • 22
    Patil N., Cox DR., Bhat D., Faham M., Myers RM., Peterson AS. A potassium channel mutation in weaver mice implicates membrane excitability in granule cell differentiation. Nature Genet 1995; 11 1269.
  • 23
    Hales TG., Lambert JJ. Modulation of GABAA and glycine receptors by chlormethiazole. Eur J Pharmacol 1992; 210 23946.
  • 24
    Holland KD., Bouley MG., Covey DF., Ferrendelli JA. Alkyl-substituted gamma-butyrolactones act at a distinct site allosterically linked to the TBPS/picrotoxinin site on the GABAA receptor complex. Brain Res 1993; 615 1704.
  • 25
    Kokate TG., Svennson BE., Rogawski MA. Anticonvulsant activity of neurosteroids: correlation with gamma-aminobutyric acid-evoked chloride current potentiation. J Pharmacol Exp Ther 1994; 270 12239.
  • 26
    Kume A., Greenfield LJ., Macdonald RL., Albin RL. Felbamate inhibits [3H]t-butylbicycloorthobenzoate (TBOB) binding and enhances CI- current at the gamma-aminobutyric acid A (GABAA) receptor. J Pharmacol Exp Ther 1996; 277 178492.
  • 27
    Wafford KA., Bain CJ., Quirk K., et al. A novel allosteric modulatory site on the GABAA receptor beta-subunit. Neuron 1994; 12 77582.
  • 28
    Im HK., Im WB., Hamilton BJ., Carter DB., VonVoigtlander PF. Potentiation of -γ-aminobutyric acid-induced chloride currents by various benzodiazepine site agonists with the α1γ2, β2γ2 and α1β2γ2 subtypes of cloned γ-aminobutyric acid type A receptors. Mol Pharmacol 1993; 44 86670.
  • 29
    McKernan RM., Wafford K., Quirk K., et al. The pharmacology of the benzodiazepine site of the GABA-A receptor is dependent on the type of gamma-subunit present. J Recept Res 1995; 15 17383.
  • 30
    Pribilla I., Neuhaus R., Hiba R., et al. Abecarnil is a full agonist at some, and a partial agonist at other recombinant GABAA receptor subtypes. Psychopharmacol Ser 1993; 11 5061.
  • 31
    Sieghart W. Structure and pharmacology of gamma-aminobutyric acidA receptor subtypes. Pharmacol Rev 1995; 47 181234.
  • 32
    Wisden W., Laurie DJ., Monyer H., Seeburg PH. The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. I. Telencephalon, diencephalon, mesencephalon. J Neurosci 1992; 12 104062.
  • 33
    Tyndale RF., Hales TG., Olsen RW., Tobin AJ. Distinctive patterns of GABAA receptor subunit mRNAs in 13 cell lines. J Neurosci 1994; 14 541728.
  • 34
    Onoe H., Tsukada H., Nishiyama S., et al. A subclass of GABAA/ benzodiazepine receptor exclusively localized in the limbic system. Neuroreport 1996; 8 11722.
  • 35
    Tretter V., Ehya N., Fuchs K., Sieghart W. Stoichiometry and assembly of a recombinant GABAA receptor subtype. J Neurosci 1997; 17 272837.
  • 36
    Hollmann M., Heinemann S. Cloned glutamate receptors. Annu Rev Neurosci 1994; 17 31108.
  • 37
    Hess SD., Daggett LP., Crona J., et al. Cloning and functional characterization of human heteromeric N-methyl-D-aspartate receptors. J Pharmacol Exp Ther 1996; 278 80816.
  • 38
    Ilyin VI., Whittemore ER., Guastella J., Weber E., Woodward RM. Subtype-selective inhibition of N-methyl-D-aspartate receptors by haloperidol. Mol Pharmacol 1996; 50 154150.
  • 39
    Chapman AG., Meldrum BS. Non-competitive N-methyl-D-aspartate antagonists protect against sound-induced seizures in DBA/2 mice. Eur J Pharmacol 1989; 166 20111.
  • 40
    Meldrum BS., Chapman AG. Competitive NMDA antagonists as drugs. In: Watkins, JC., Collingridge, GL.. The NMDA receptor., Oxford : IRL Press, 1994; 455.
  • 41
    Geiger JRP., Melcher T., Koh D-S, et al. Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS. Neuron 1995; 15 193204.
  • 42
    Lomeli H., Mosbacher J., Melcher T., et al. Control of kinetic properties of AMPA receptor channels by nuclear RNA editing. Science 1994; 266 170913.
  • 43
    Chapman AG., Smith SE., Meldrum BS. The anticonvulsant effect of the non-NMDA antagonists, NBQX and GYKI 52466, in mice. Epilepsy Res 1991; 9 926.
  • 44
    Brusa R., Zimmermann F., Koh DS., et al. Early-onset epilepsy and postnatal lethality associated with an editing-deficient GluR-B allele in mice. Science 1995; 270 167780.
  • 45
    Bleakman D., Schoepp DD., Ballyk B., et al. Pharmacological discrimination of GluR5 and GluR6 kainate receptor subtypes by (3S,4aR,6R,8aR)-6-[2-(l(2)H-tetrazole-5-yI)ethyl]decahydroiso-quinoline-3 carboxylic acid. J Pharmacol Exp Ther 1996; 49 5815.
  • 46
    Pin, J-P, Duvoisin R. The metabotropic giutamate receptors: structure and functions. Neuropharmacology 1995; 34 126.
  • 47
    Tizzano JP., Griffey KI., Schoepp DD. Induction or protection of limbic seizures in mice by mGlu subtype selective agonists. Neuropharmacology 1995; 34 10637.
  • 48
    Thomsen C., Klitgaard H., Sheardown M., et al. (S)-4-carboxy-3-hydroxphenylglycine, an antagonist of metabotropic giutamate receptor (mGluR)la and an agonist of mGluR2, protects against audiogenic seizures in DBA/2 mice. J Neurochem 1994; 62 24925.
  • 49
    Ghauri M., Chapman AG., Meldrum BS. Convulsant and anticonvulsant actions of agonists and antagonists of group II mGluRs. Neuroreport 1996; 7 146974.
  • 50
    Tang E., Yip PK., Chapman AG., Jane DE., Watkins JC., Meldrum BS. Prolonged anticonvulsant action of giutamate metabotropic agonists in inferior colliculus of genetically epilepsy-prone rats. Eur J Pharmacol 1997; 327 10915.
  • 51
    Borden LA., Dhar TGM., Smith KE., Weinshank RL., Branchek TA., Gluchowski C. Tiagabine, SK & F 89976-A, CI-966, and NNC-711 are selective for the cloned GAB A transporter GAT-1. Eur J Pharmacol Mol Pharmacol 1994; 269 21924.
  • 52
    Mengel H. Tiagabine. Epilepsia 1994; 35 (suppl 5): S814.
  • 53
    Suzdak PD., Jansen JA. A review of the preclinical pharmacology of tiagabine: a potent and selective anticonvulsant GABA uptake inhibitor. Epilepsia 1995; 36 61226.
  • 54
    Dalby NO., Thomsen C., Fink-Jensen A., et al. Anticonvulsant properties of two GABA uptake inhibitors NNC 05–2045 and NNC 05–2090 not acting preferentially on GAT1. Epilepsy Res 1997 ,28:51–62.
  • 55
    Scanziani M., Salin PA., Vogt KE., Malenka RC., Nicoll RA. Use-dependent increases in giutamate concentration activate presynaptic metabotropic giutamate receptors. Nature 1997; 385 6304.
  • 56
    Millan MH., Chapman AG., Meldrum BS. Extracellular amino acid levels in hippocampus during pilocarpine-induced seizures. Epilepsy Res 1993; 14 13948.
  • 57
    Hausser M., Roth A. Dendritic and somatic giutamate receptor channels in rat cerebellar Purkinje cells. J Physiol 1997; 501 7795.
  • 58
    Amara SG., Kuhar MJ. Neurotransmitter transporters: recent progress. Annu Rev Neurosci 1993; 16 7393.
  • 59
    Ma E., Haddad GG. Expression and localization of Na+/H+ exchangers in rat central nervous system. Neuroscience 1997; 79 591603.
  • 60
    Lippert B., Metcalf BW., Jung MJ., Casara P. 4-amino-hex-5-enoic acid, a selective catalytic inhibitor of 4-aminobutyric acid aminotransferase in mammalian brain. Eur J Biochem 1977; 74 4415.
  • 61
    Staley KJ., Soldo BL., Proctor WR. Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. Science 1995; 269 97781.
  • 62
    Meldrum BS., Horton RW. Neuronal inhibition mediated by GABA and patterns of convulsions in baboons with photosensitive epilepsy (Papio papio). In: HarrisP., MawdsleyC. Epilepsy., Edinburgh : Churchill Livingstone, 1974; 5564.
  • 63
    Hosford DA. Models of primary generalized epilepsy. Curr Opin Neurol 1995; 8 1215.
  • 64
    Hosford DA., Wang Y. Utility of the lethargic (lh/lh) mouse model of absence seizures in predicting the effects of lamotrigine, viga-batrin, tiagabine, gabapentin, and topiramate against human absence seizures. Epilepsia 1997; 38 40814.
  • 65
    Hosford DA., Clark S., Cao Z., et al. The role of GABAB receptor activation in absence seizures of lethargic (lh/lh) mice. Science 1992; 257 398401.
  • 66
    Snead OC. Presynaptic GABAB and gamma-hydroxybutyric acid-mediated mechanisms in generalised absence seizures. Neuropharmacology 1996; 35 35967.
  • 67
    Fletcher CF., Lutz CM., O'Sullivan TM., et al. Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Cell 1996; 87 60717.
  • 68
    Burgess DL., Jones JM., Meisler MH., Noebels JL. Mutations of the Ca2+ channel beta subunit gene Cchb4 is associated with ataxia and seizures in the lethargic (In) mouse. Cell 1997; 88 38592.
  • 69
    Gillard SE., Volsen SG., Smith W., Beattie RE., Bleakman D., Lodge D. Identification of pore-forming subunit of P-type calcium channels: an antisense study on rat cerebellar Purkinje cells in culture. Neuropharmacology 1997; 36 4059.
  • 70
    Meldrum BS. Update on the mechanism of action of antiepileptic drugs. Epilepsia 1996; 37 (suppl 6): S411.
  • 71
    Barrantes GE., Ortells MO., Ban-antes FJ. Screening structural-functional relationships of neuropharmacologically active organic compounds at the nicotinic acetylcholine receptor. Neuropharmacology 1997; 36 26979.
  • 72
    Hogan, JC. Jr. Directed combinatorial chemistry. Nature 1996 ,384: 17–22.
  • 73
    Akiyama K., Daigen A., Yamada N., et al. Long-lasting enhancement of metabotropic excitatory amino acid receptor-mediated polyphosphoinositide hydrolysis in the amygdala/pyriform cortex of deep prepiriform cortical kindled rats. Brain Res 1992; 569 717.
  • 74
    During MJ., Ryder KM., Spencer DD. Hippocampal GABA transporter function in temporal-lobe epilepsy. Nature 1995; 376 1747.
  • 75
    Kohr G., de Koninck Y., Mody I. Properties of NMDA receptor channels in neurons acutely isolated from epileptic (kindled) rats. J Neurosci 1993; 13 361227.
  • 76
    Mody I. The molecular basis of kindling. Brain Pathol 1993 3: 395^03.
  • 77
    Noebels JL. Targeting epilepsy genes. Neuron 1996; 16 2414.
  • 78
    Pennacchio LA., Lehesjoki AE., Stone NE., et al. Mutations in the gene encoding cystatin B in progressive myoclonus epilepsy (EPM1). Science 1996; 271 17314.
  • 79
    Lalioti MD., Mirotsou M., Buresi C., et al. Identification of mutations in cystatin B, the gene responsible for the Unverricht-Lundborg type of progressive myoclonus epilepsy (EPM1). Am J Hum Genet 1997; 60 34251.
  • 80
    Noebels JL. A single gene error in noradrenergic axon growth synchronizes central neurons. Nature 1994; 310 40911.
  • 81
    Beck H., Moulard B., Steilein U., et al. A nonsense mutation in the alpha4 subunit of the nicotinic acetylcholine receptor (CHRNA4) cosegregates with 20q-linked benign neonatal familial convulsions. (EHN1). Neurobiot Dis 1994; 1 959.
  • 82
    Forman SA., Yellen G., Thiele EA. Alternative mechanism for pathogenesis of an inherited epilepsy by a nicotinic AChR mutation. Nature Genet 1996; 13 3967.
  • 83
    Weiland S., Witzemann V., Villarroel A., Propping P., Steinlein U. An amino acid exchange in the second transmembrane segment of a neuronal nicotinic receptor causes partial epilepsy by altering its desensitization kinetics. FEBS Lett 1996; 398 916.
  • 84
    Tsirka SE., Gualandris A., Amaral DG., Strickland S. Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue plasminogen activator. Nature 1995; 377 3404.
  • 85
    Cain DP., Gant SGN., Saucier D., Hargreaves EL., Kandel ER. Fyn tyrosine kinase is required for normal amygdala kindling. Epilepsy Res 1995; 22 10714.
  • 86
    Kokaia M., Ernfors P., Kokaia Z., Elmer E., Jaenisch R., Linvall O. Suppressed epileptogenesis in BDNF mutant mice. Exp Neurol 1995; 133 21524.
  • 87
    Sveinbjornsdottir S., Sander JWAS., Upton D., et al. The excitatory amino acid antagonist D-CPP-ene (SDZ EAA-494) in patients with epilepsy. Epilepsy Res 1993; 16 16574.
  • 88
    Honavar M., Meldrum BS. Epilepsy. In: Graham, DI., Lantos, PL.. Greenfield's neuropathology., 6th ed. London : Arnold, 1997; 93171.
  • 89
    Meldrum BS. Epileptic brain damage: a consequence and a cause of seizures. The first Alfred Meyer Memorial Lecture. Neuropathol Appl Neurobiol 1997; 23 185202.
  • 90
    Gall CM, Isackson PJ. Limbic seizures increase neuronal production of messenger RNA for nerve growth factor. Science 1989; 245 75861.
  • 91
    Bengzon J., Soderstrom S., Kokaia Z., et al. Widespread increase of nerve growth factor protein in the rat forebrain after kindling-induced seizures. Brain Res 1992 587:338^t2.
  • 92
    Thoenen H. Neurotrophins and neuronal plasticity. Science 1995; 270 5938.
  • 93
    Van der Zee CEEM., Rashid K., Le K., et al. Intraventricular administration of antibodies to nerve growth factor retards kindling and blocks mossy fiber sprouting in adult rats. J Neurosci 1995; 15 531623.
  • 94
    Martinez-Serrano A., Bjorklund A. Protection of the neostriatum against excitotoxic damage by neurotrophin-producing, genetically modified neural stem cells. J Neurosci 1996; 16 460416.
  • 95
    Hyman SE. Regulation of gene expression of neural signals. Neu-roscientist 1996; 2 21724.
  • 96
    Kiessling M., Gass P. Immediate early gene expression in experimental epilepsy. Brain Pathol 1993; 3 38193.
  • 97
    During MJ., Mirchandani GR., Leone P., et al. Direct hippocampal injection of a HSV-1 vector expressive GLUR6 results in spontaneous seizures, hyperexcitability in CA1 cells and loss of CA1, hilar and CA3 neurons [Abstract]. Soc Neurosci Abstr 1993; 19 21.