Epilepsy Research
Volume 23, Issue 1 , Pages 1-14 , February 1996

Remacemide HC1 and its metabolite, FPL 12495AA, limit action potential firing frequency and block NMDA responses of mouse spinal cord neurons in cell culture

  • Artur W. Wamil

      Affiliations

    • Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
    • Current address: Department of Anesthesiology, VUMC, 1161 21st Avenue South, T-4216 Medical Center North, Nashville, TN 37232-2125, USA. Tel.: (615) 322-4000; fax (615) 322-7446.
  • ,
  • Helen Cheung

      Affiliations

    • Department of Biology, Astra Arcus USA, P.O. Box 20890, Rochester, NY 14602, USA
  • ,
  • Eric W. Harris

      Affiliations

    • Department of Biology, Astra Arcus USA, P.O. Box 20890, Rochester, NY 14602, USA
  • ,
  • Michael J. McLean

      Affiliations

    • Corresponding Author InformationCorresponding author. Department of Neurology, VUMC, 2100 Pierce Avenue, 351 MCS Nashville, TN 37212, USA. Tel.: (615) 936-0060; fax: (615) 936-0223.
    • Department of Neurology, Veterans Administration Medical Center, Nashville, TN, USA
    • Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA

Received 22 February 1993 ,Revised 21 March 1995 ,Accepted 31 July 1995.

References 

  1. 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
  2. Clineschmidt BV, Martin GE, Bunting PR. Anti-convulsant activity of (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d) cyclohepten-5,10-imine (MK-801), a substance with potent anticonvulsant, central sympathomimetic, and apparent anxiolytic properties. Drug. Dev. Res. 1982;2:123–134
  3. Courtney KR, Etter EG. Modulated anticonvulsant block of sodium channels in nerve and muscle. Eur. J. Pharmacol. 1983;88:1–9
  4. Crawford P, Richens A, Mawer G, Cooper P, Hutchison JB. A double-blind placebo controlled cross-over study of remacemide hydrochloride as adjunctive therapy in patients with refractory epilepsy. Seizure. 1992;1(suppl. A):7–13
  5. Foot M, Wallace J, Gabapentin . In:  Pisani F,  Perucca E,  Avanzini G,  Richens A editor. New Antiepileptic Drugs. Amsterdam: Elsevier Science Publishers; 1991;p. 104–109
  6. Garske GE, Palmer GC, Napier JJ, Griffith RC, Freedman LR, Harris EW, et al. Preclinical profile of the anticonvulsant remacemide and its enantiomers in the rat. Epilepsy Res. 1991;9:161–174
  7. Halliwell RF, Peters JA, Lambert JJ. The mechanism of action and pharmacological specificity of the anticonvulsant NMDA antagonist MK-801: A voltage clamp study on neuronal cells in culture. Br. J. Pharmacol. 1989;96:480–494
  8. Harris E, Stagnitto M, Garske G, Cregan E, Ray R, Julien R, et al. Neuroprotection by remacemide, a prodrug for noncompetitive NMDA antagonism with a high therapeutic index. In:  Kamenka J-M,  Domino EF editor. Multiple Sigma and PCP Ligands: Mechanism for Neuromodulation and Neuroprotection?. Ann Arbor, MI: NPP Books; 1992;p. 643–653
  9. Heyer EJ, Macdonald RL. Calcium- and sodium-dependent action potentials of mouse spinal cord and dorsal root ganglion neurons in cell culture. J. Neurophysiol. 1982;47:641–655
  10. Heyn H, McCarthy DJ, Curry SH, Eisman MS, Anders MW. Brain uptake and biotransformation of remacemide hydrochloride, a novel anticonvulsant. Drug Metab. Dispos. 1994;22(3):443–446
  11. Hollander M, Wolfe DA. The dichotomous data problem. In:  Bradley RA,  Hunter JS,  Kendall DG,  Watson GS editor. Non-parametric Statistical Methods. New York: John Wiley and Sons; 1973;p. 15–25
  12. Hutchison J. Remecemide hydrochloride: A novel antiepileptic drug. In: Progress Report on New Antiepileptic Drugs, Program and Abstract. Eilat, Israel, May 31–June 2. 1992;p. 21
  13. Krall RL, Penry JK, White BG, Kupferberg HJ, Swinyard EA. Antiepileptic drug development. II. Anticonvulsant drug screening. Epilepsia. 1978;19:409–428
  14. Lampe H, Bigalke H. Carbamazepinne blocks NMDA-activated currents in spinal cord cord neurons. NeuroReport. 1990;1:26–28
  15. Litchfield JT, Wilcoxon F. A simplified method of evaluating dose-effect experiments. J. Pharmacol. Exp. Ther. 1949;96:99–113
  16. Löscher W, Schmidt D. Which animal models should be used in the search for new antiepileptic drugs? A proposal base on experimental and clinical considerations. Epilepsy Res. 1988;2:145–181
  17. McLean MJ, Macdonald RL. Multiple actions of phenytoin on mouse spinal cord neurons in cell culture. J. Pharmacol. Exp. Ther. 1983;227:779–789
  18. McLean MJ, Macdonald RL. 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;237:1001–1011
  19. McLean MJ, Macdonald RL. Carbamazepine and 10,11-epoxycarbamazepine produce use- and voltage-dependent limitation of rapidly firing of action potentials of mouse central neurons in cell culture. J. Pharmacol. Exp. Ther. 1986;238:727–738
  20. Muir KT, Palmer GC. Remacemide. In:  Pisani F,  Perucca E,  Avanzini G,  Richens A editor. New Antiepileptic Drugs. Amsterdam: Elsevier Science Publishers; 1991;p. 147–152 (Epilepsy Res. Suppl. 3)
  21. Palmer GC, Stagnitto ML, Ordy JM, Griffith RC, Napier JJ, Gentile RJ, et al. Preclinical profile of stereoisomers of the anticonvulsant remacemide in mice. Epilepsy Res. 1991;8:36–48
  22. Palmer GC, Harris EW, Ray R, Stagnitto ML, Schmiesing RJ. Classification of compounds for prevention of NMDLA-induced seizures/mortality, or maximal electroshock and pentylenetretazol seizures in mice and antagonisms of MK-801 biding in vitro. Arch. Int. Pharmacodyn. 1992;317:16–34
  23. Palmer GC, Murray RJ, Wilson TCM, Eisman MS, Ray RK, Griffith RC, et al. Biological profile of the metabolites and potential metabolites of the anticonvulsant remacemide. Epilepsy Res. 1992;12:9–20
  24. Ragsdale DS, Scheuer T, Catterall WA. Frequency and voltage-dependent inhibition of type IIA Na+ channels, expressed in a mammalian cell line, by local anesthetic, antiarrhythmic, and anticonvulsant drugs. Mol. Pharmacol. 1991;40:756–765
  25. Rho JM, Donevan SD, Rogawski MA. Mechanism of action of the anticonvulsant felbamate: Opposing effects on N-methyl-d-aspartate and γ-aminobutyric acidA receptors. Ann. Neurol. 1994;35:229–234
  26. Riederer P, Lange KW, Kornhuber J, et al.  Glutamate receptor antagonism: Neurotoxicity, anti-akinetic effects, and psychosis. J. Neural Transm. 1991;34(S):203–210
  27. Rothman S. Noncompetitive N-methyl-d-aspartate antagonists affect multiple ionic currents. J. Pharmacol. Exp. Ther. 1988;246:137–142
  28. Schauf GL, Floyd AD, Marder J. Effects of carbamazepine in the ionic conductances of myxicola giant axons. J. Pharmacol. Exp. Ther. 1974;189:538–543
  29. Scheyer RD, Cramer JA, Leppik IE, Pellock JM, Hochholzer JM, et al.  Remacemide elimination after initial and chronic dosing. Clin. Pharmacol. Ther. 1992;51:189
  30. Schwartz J, Vogel W. Diphenylhydantoin excitability reducing action in single myelinated nerve fibers. Eur. J. Pharmacol. 1977;44:241–249
  31. Stagnitto ML, Palmer GC, Ordy JM, Griffith RC, Napier JJ, Becker CN, et al. Preclinical profile of remacemide: A novel anticonvulsant effective against maximal electroshock seizures in mice. Epilepsy Res. 1990;7:11–28
  32. Subramaniam S, Donevan SD, Rogawski MA. 1,2-Diphenyl-2-propylamine, a major metabolite of the anticonvulsant remacemide, produces a stereoselective block of NMDA receptor currents. Neurosci. Abstr. 1993;19:717
  33. Sveinbjornsdottir S, Sander JWAS, Upton D, Thompson PJ, Patsalos PN, Hirt D, et al. The excitatory amino acid antagonist D-CPP-ene (SDZ EAA-494) in patients with epilepsy. Epilepsy Res. 1993;16:165–174
  34. Taylor CP. The anticonvulsant lamotrigine blocks sodium currents from cloned alpha-subunits of rat brain Na channels in a voltage-dependent manner, but gabapentin does not. Soc. Neurosci. Abstr. 1993;19:1631
  35. Van den Berg RJ, Kok P, Voskuyl RA. Valproate and sodium currents in cultured hippocampal neurons. Exp. Brain Res. 1993;93:279–287
  36. VanDongen AMJ, Van Erp MG, Voskuyl RA. Valproate reduces excitability by blockade of sodium and potassium conductance. Epilepsia. 1986;27:177–182
  37. Wamil AW, McLean MJ. Effect of anticonvulsant medications on responses to NMDA by mouse central neurons in cell culture. Epilepsia. 1991;32(Suppl. 3):42
  38. Wamil AW, McLean MJ. Use-, concentration- and voltage-dependent limitation by MK-801 of action potential firing frequency in mouse central neurons in cell culture. J. Pharmacol. Exp. Ther. 1992;260:376–383
  39. Wamil AW, McLean MJ. Phenytoin blocks N-methyl-d-aspartate responses of mouse central neurons. J. Pharmacol. Exp. Ther. 1993;267:218–227
  40. Wamil AW, McLean MJ. Effect of temperature on limitation by MK-801 of firing of action potentials by spinal cord neurons in cell culture. Eur. J. Pharmacol. 1993;230:263–269
  41. Wamil AW, McLean MJ. Limitation of gabapentin of high frequency action potential firing by mouse central neurons in cell culture. Epilepsy Res. 1994;17:1–11
  42. Wamil AW, Schmutz M, Portet C, Feldmann KF, McLean MJ. Effects of oxcarbazepine and 10-hydroxycarbamazepine on action potential firing and generalized seizures. Eur. J. Pharmacol. 1994;271:301–308
  43. Wilder BJ, Buchanan RA, Serrano EE. Correlation of acute diphenylhydantioin intoxication with plasma levels and metabolite excretion. Neurology. 1973;23:1329–1333
  44. Wilson TCM, Machulskis GE, Garske GE, Harris EW. Anticonvulsant concentrations in CSF and serum of rats protected against MES by PR934-423A. Soc. Neurosci Abstr. 1988;14:1034
  45. 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;81:313–317

PII: 0920-1211(95)00053-4

Epilepsy Research
Volume 23, Issue 1 , Pages 1-14 , February 1996