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Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity

Molecular Psychiatry volume 7, pages 726–733 (2002)Cite this article

Abstract

N-methyl-D-aspartate (NMDA) glutamate receptor antagonists are used in clinical anesthesia and are being developed as therapeutic agents for preventing neurodegeneration in stroke, epilepsy, and brain trauma. However, the ability of these agents to produce neurotoxicity in adult rats and psychosis in adult humans compromises their clinical usefulness. In addition, an NMDA receptor hypofunction (NRHypo) state might play a role in neurodegenerative and psychotic disorders, like Alzheimer's disease, bipolar disorder and schizophrenia. Thus, developing pharmacological means of preventing these NRHypo-induced effects could have significant clinically relevant benefits. NRHypo neurotoxicity appears to be mediated by a complex disinhibition mechanism that results in the excessive stimulation of certain vulnerable neurons. Here we report our findings that five agents (phenytoin, carbamazepine, valproic acid, lamotrigine, and riluzole), thought to possess anticonvulsant activity because they inhibit voltage-gated sodium channels, prevent NRHypo neurotoxicity. The ability of tetrodotoxin, a highly selective inhibitor of voltage-gated sodium channels, to prevent the same neurotoxicity suggests that inhibition of this ion channel is the likely mechanism of action of these five agents. We also found that three other anticonvulsants (felbamate, gabapentin and ethosuximide), whose mechanism is less clear, also prevent NRHypo neurotoxicity, suggesting that inhibition of voltage-gated sodium channels is not the only mechanism via which anticonvulsants can act to prevent NRHypo neurotoxicity. Several of these agents have been found to be of clinical use in bipolar disorder. It would be of interest to determine whether these agents might have therapeutic benefits for conditions in which a NRHypo state may exist.

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References

  1. Domino EF, Luby ED . Abnormal mental states induced by phencyclidine as a model of schizophrenia. In: Domino EF (ed) PCP (Phencyclidine): Historical and Current Perspectives NPP Books: Ann Arbor 1981; 401–418

    Google Scholar 

  2. Javitt DC, Zukin SR . Recent advances in the phencyclidine model of schizophrenia Am J Psychiatry 1991; 148: 1301–1308

    Article  CAS  Google Scholar 

  3. Olney JW, Farber NB . Glutamate receptor dysfunction and schizophrenia Arch Gen Psychiatry 1995; 52: 998–1007

    Article  CAS  Google Scholar 

  4. Farber NB, Newcomer JW . The role of NMDA receptor hypofunction in idiopathic psychotic disorders. In: Geller B, Delbello M (eds). Child and Early Adolescent Bipolar Disorder Guilord Publications: New York 2002 (in press)

  5. Anand A, Charney DS, Oren DA, Berman RM, Hu XS, Cappiello A et al. Attenuation of the neuropsychiatric effects of ketamine with lamotrigine Arch Gen Psychiatry 2000; 57: 270–276

    Article  CAS  Google Scholar 

  6. Wenk GL, Walker LC, Price DL, Cork LC . Loss of NMDA, but not GABA-A, binding in the brains of aged rats and monkeys Neurobiol Aging 1991; 12: 93–98

    Article  CAS  Google Scholar 

  7. Ulas J, Cotman CW . Decreased expression of N-methyl-D-aspartate receptor 1 messenger RNA in select regions of Alzheimer brain Neuroscience 1997; 79: 973–982

    Article  CAS  Google Scholar 

  8. Olney JW, Wozniak DF, Farber NB . Excitotoxic neurodegeneration in Alzheimer disease; new hypothesis and new therapeutic strategies Arch Neurol 1997; 54: 1234–1240

    Article  CAS  Google Scholar 

  9. Olney JW, Labruyere J, Price MT . Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs Science 1989; 244: 1360–1362

    Article  CAS  Google Scholar 

  10. Paxinos G, Watson C . The Rat Brain in Stereotaxic Coordinates, 4th edn Academic Press: New York 1998

    Google Scholar 

  11. Vogt BA . Structural organization of cingulate cortex: areas,neurons, and somatodendritic transmiter receptors In: Vogt BA,Gabriel M (eds) Neurobiology of Cingulate Cortex and Limbic Thalamus Birkhauser: Boston 1993; pp 19–70

    Chapter  Google Scholar 

  12. Allen HL, Iversen LL . Phencyclidine, dizocilpine, and cerebrocortical neurons Science 1990; 247: 221

    Article  CAS  Google Scholar 

  13. Olney JW, Labruyere J, Wang G, Wozniak DF, Price MT, Sesma MA . NMDA antagonist neurotoxicity: mechanism and prevention Science 1991; 254: 1515–1518

    Article  CAS  Google Scholar 

  14. Ellison G, Switzer RC . Dissimilar patterns of degeneration in brain following four different addictive stimulants Neuroreport 1993; 5: 17–20

    Article  CAS  Google Scholar 

  15. Corso TD, Sesma MA, Tenkova TI, Der TC, Wozniak DF, Farber NB et al. Multifocal brain damage induced by phencyclidine is augmented by pilocarpine Brain Res 1997; 752: 1–14

    Article  CAS  Google Scholar 

  16. Horvath ZC, Czopf J, Buzsaki G . MK-801-induced neuronal damage in rats Brain Res 1997; 753: 181–195

    Article  CAS  Google Scholar 

  17. Farber NB, Kim SH, Dikranian K, Jiang XP, Heinkel C . Receptor mechanisms and circuitry underlying NMDA antagonist neurotoxicity Mol Psychiatry 2002; 7: 32–43

    Article  CAS  Google Scholar 

  18. Jiang XP, Dikranian K, Farber NB . Muscimol prevents NMDA antagonist neurotoxicity by acting at GABAergic receptors in the diagonal band and anterior thalamus Soc Neurosci Abs 2001; 27: 973.4

    Google Scholar 

  19. Macdonald RL . Cellular effects of antiepileptic drugs In: Engel J, Pedley TA (eds) Epilepsy: A Comprehensive Textbook Lippincott-Raven Publishers: Philadelphia 1997; pp 1383–1391

    Google Scholar 

  20. Prakriya M, Mennerick S . Selective depression of low-release probability excitatory synapses by sodium channel blockers Neuron 2000; 26: 671–682

    Article  CAS  Google Scholar 

  21. Zona C, Siniscalchi A, Mercuri NB, Bernardi G . Riluzole interacts with voltage-activated sodium and potassium currents in cultured rat cortical neurons Neuroscience 1998; 85: 931–938

    Article  CAS  Google Scholar 

  22. Taylor CP, Meldrum BS . NA+ channels as targets for neuroprotective drugs Trends Pharmacol Sci 1995; 16: 309–316

    Article  CAS  Google Scholar 

  23. Takata M, Moore JW, Kao CY, Fuhrman FA . Blockage of sodium conductance increase in lobster giant axon by tarichatoxin (tetrodotoxin) J Gen Physiol 1966; 49: 977–988

    Article  CAS  Google Scholar 

  24. Moore JW, Blaustein MP, Anderson NC, Narahashi T . Basis of tetrodotoxin's selectivity in blockage of squid axons J Gen Physiol 1967; 50: 1401–1411

    Article  CAS  Google Scholar 

  25. Macdonald RL, Greenfield LJ . Mechanism of action of new antiepileptic drugs Curr Opin Neurol 1997; 10: 121–128

    Article  CAS  Google Scholar 

  26. Jevtovic-Todorovic V, Kirby CO, Olney JW . Isoflurane and propofol block neurotoxicity caused by MK-801 in the rat posterior cingulate/retrosplenial cortex J Cereb Blood Flow Metab 1997; 17: 168–174

    Article  CAS  Google Scholar 

  27. Swinyard EA, Sofia RD, Kupferberg HJ . Comparitive anticonvulsant activity and neurotoxicity of felbamate and four prototype antiepileptic drugs in mice and rats Epilepsia 1986; 27: 27–34

    Article  CAS  Google Scholar 

  28. Mizoule J, Meldrum B, Mazadier M, Croucher M, Ollat C, Uzan A et al. 2-Amino-6-trifluoromethoxy benzothiazole, a possible antagonist of excitatory amino acid transmission – I anticonvulsant properties Neuropharmacology 1995; 24: 767–773

    Article  Google Scholar 

  29. 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

    Article  CAS  Google Scholar 

  30. Taglialatela M, Ongini E, Brown AM, Di Renzo G, Annunziato L . Felbamate inhibits cloned voltage-dependent Na+ channels from human and rat brain Eur J Pharmacol 1996; 316: 373–377

    Article  CAS  Google Scholar 

  31. McCabe RT, Wasterlain CG, Kucharczyk N, Sofia RD, Vogel JR . Evidence for anticonvulsant and neuroprotectant action of felbamate mediated by strychnine-insensitive glycine receptors J Pharmacol Exp Therapeut 1993; 264: 1248–1252

    CAS  Google Scholar 

  32. Rho JM, Donevan SD, Rogawski MA . Mechanism of action of the anticonvulsant felbamate: opposing effects on N-methyl-D-aspartate and gamma-aminobutyric acidA receptors Ann Neurol 1994; 35: 229–234

    Article  CAS  Google Scholar 

  33. Lowe DA, Emre M, Frey P, Kelly PH, Malanowski J, McAllister KH et al. The pharmacology of SDZ EAA 494, a competitive NMDA antagonist Neurochem Int 1994; 25: 583–600

    Article  CAS  Google Scholar 

  34. Zarnowski T, Kleinrok Z, Turski WA, Czuczwar SJ . The competitive NMDA antagonist, D-CPP-ene, potentiates the anticonvulsant activity of conventional antiepileptics against maximal electroshock-induced seizures in mice Neuropharmacology 1994; 33: 619–624

    Article  CAS  Google Scholar 

  35. Urbanska E, Dziki M, Kleinrok Z, Czuczwar SJ, Turski WA . Influence of MK-801 on the anticonvulsant activity of antiepileptics Eur J Pharmacol 1991; 200: 277–282

    Article  CAS  Google Scholar 

  36. Schoepp DD, Ornstein PL, Leander JD, Lodge D, Salhoff CR, Zeman S et al. Pharmacological characterization of LY233053: a structurally novel tetrazolesubstituted competitive N-methyl-D-aspartic acid antagonist with a short duration of action J Pharmacol Exp Therapeut 1990; 255: 1301–1308

    CAS  Google Scholar 

  37. Chadwick DC, Browne TR . Gabapentin In: Engel J, Pedley TA (eds) Epilepsy: A Comprehensive Textbook Lippincott-Raven Publishers: Philadelphia 1997; pp 1521–1530

    Google Scholar 

  38. Ishimaru M, Fukamauchi F, Olney JW . Halothane prevents MK-801 neurotoxicity in the rat cingulate cortex Neurosci Lett 1995; 193: 1–4

    Article  CAS  Google Scholar 

  39. Farber NB, Newcomer JW, Olney JW . Glycine agonists: what can they teach us about schizophrenia? Arch Gen Psychiatry 1999; 56: 13–17

    Article  CAS  Google Scholar 

  40. Tekin S, Aykut-Bingol C, Tanridag T, Aktan S . Antiglutamatergic therapy in Alzheimer's disease—effects of lamotrigine J Neural Transm Suppl 1998; 105: 295–303

    Article  CAS  Google Scholar 

  41. Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD . A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. Lamictal 602 Study Group J Clin Psychiatry 1999; 60: 79–88

    Article  CAS  Google Scholar 

  42. Calabrese JR, Suppes T, Bowden CL, Sachs GS, Swann AC, McElroy SL et al. A double-blind, placebo-controlled, prophylaxis study of lamotrigine in rapid-cycling bipolar disorder. Lamictal 614 Study Group J Clin Psychiatry 2000; 61: 841–850

    Article  CAS  Google Scholar 

  43. Calabrese JR, Gajwani P . Lamotrigine and clozapine for bipolar disorder Am J Psychiatry 2000; 157: 1523

    Article  CAS  Google Scholar 

  44. Lerer B, Moore N, Meyendorff E, Cho SR, Gershon S . Carbamazepine versus lithium in mania: a double-blind study J Clin Psychiatry 1987; 48: 89–93

    CAS  PubMed  Google Scholar 

  45. Small JG, Klapper MH, Milstein V, Kellams JJ, Miller MJ, Marhenke JD et al. Carbamazepine compared with lithium in the treatment of mania Arch Gen Psychiatry 1991; 48: 915–921

    Article  CAS  Google Scholar 

  46. Greil W, Kleindienst N . Lithium versus carbamazepine in the maintenance treatment of bipolar II disorder and bipolar disorder not otherwise specified Int Clin Psychopharmacol 1999; 14: 283–285

    Article  CAS  Google Scholar 

  47. Greil W, Kleindienst N . The comparative prophylactic efficacy of lithium and carbamazepine in patients with bipolar I disorder Int Clin Psychopharmacol 1999; 14: 277–281

    Article  CAS  Google Scholar 

  48. Pope HG, McElroy SL, Keck PE, Hudson JI . Valproate in the treatment of acute mania. A placebo-controlled study Arch Gen Psychiatry 1991; 48: 62–68

    Article  Google Scholar 

  49. Bowden CL, Brugger AM, Swann AC, Calabrese JR, Janicak PG, Petty F et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. (erratum appears in JAMA 1994; 271: 1830) JAMA 1994; 271: 918–924

    Article  CAS  Google Scholar 

  50. Bowden CL, Calabrese JR, McElroy SL, Gyulai L, Wassef A, Petty F et al. A randomized, placebo-controlled 12-month trial of dival-proex and lithium in treatment of outpatients with bipolar I disorder. Divalproex Maintenance Study Group Arch Gen Psychiatry 2000; 57: 481–489

    Article  CAS  Google Scholar 

  51. Mishory A, Yaroslavsky Y, Bersudsky Y, Belmaker RH . Phenytoin as an antimanic anticonvulsant: a controlled study Am J Psychiatry 2000; 157: 463–465

    Article  CAS  Google Scholar 

  52. Altshuler LL, Keck PE Jr, McElroy SL, Suppes T, Brown ES, Denicoff K et al. Gabapentin in the acute treatment of refractory bipolar disorder Bipolar Dis 1999; 1: 61–65

    Article  CAS  Google Scholar 

  53. Pande AC, Crockatt JG, Janney CA, Werth JL, Tsaroucha G . Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Gabapentin Bipolar Disorder Study Group Bipolar Dis 2000; 2: 249–255

    Article  CAS  Google Scholar 

  54. Ghaemi SN, Goodwin FK . Gabapentin treatment of the non-refractory bipolar spectrum: an open case series J Affect Disord 2001; 65: 167–171

    Article  CAS  Google Scholar 

  55. Binnie CD . Lamotrigine In: Engel J, Pedley TA (eds) Epilepsy: A Comprehensive Textbook Lippincott-Raven Publishers: Philadelphia 1997; pp 1531–1540

    Google Scholar 

  56. Shank RP, Gardocki JF, Streeter AJ, Maryanoff BE . An overview of the preclinical aspects of topiramate: pharmacology, pharmacokinetics, and mechanism of action Epilepsia 2000; 41(Suppl 1): S3–S9

    Article  Google Scholar 

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Acknowledgements

Supported by AG11355 from NIH.

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  1. Department of Psychiatry, Washington University, St Louis, MO, USA

    N B Farber, X-P Jiang, C Heinkel & B Nemmers

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  1. N B Farber
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Correspondence to N B Farber.

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Farber, N., Jiang, XP., Heinkel, C. et al. Antiepileptic drugs and agents that inhibit voltage-gated sodium channels prevent NMDA antagonist neurotoxicity. Mol Psychiatry 7, 726–733 (2002). https://doi.org/10.1038/sj.mp.4001087

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