Skip to main content
SpringerLink
Log in

Clinically Tolerated Strategies for NMDA Receptor Antagonism

  • Chapter
The Glutamate Receptors

Part of the book series: The Receptors ((REC))

  • 1241 Accesses

Summary

Many potentially neuroprotective drugs have failed in human clinical trials because of side effects that cause normal brain function to become compromised. An important example concerns antagonists of the N-methyl-D-aspartate type of glutamate receptor (NMDAR). Glutamate receptors are essential to the normal function of the central nervous system. However, their excessive activation by excitatory amino acids such as glutamate is thought to contribute to neuronal damage in many neurologic disorders ranging from acute hypoxic–ischemic brain injury to chronic neurodegenerative diseases such as Alzheimer disease, Parkinson disease, Huntington disease, HIV-associated dementia, multiple sclerosis, glaucoma, and amyotrophic lateral sclerosis. The dual role of NMDARs in particular for normal and abnormal functioning of the nervous system imposes important constraints on possible therapeutic strategies aimed at ameliorating neurologic diseases. Blockade of excessive NMDAR activity must therefore be achieved without interference with its normal function. In general, NMDAR antagonists can be categorized pharmacologically according to the site of action on the receptor–channel complex. These include drugs acting at the agonist (NMDA) or coagonist (glycine) sites, channel pore, and modulatory sites, such as the S-nitrosylation site, where nitric oxide (NO) reacts with critical cysteine thiol groups. Because glutamate is thought to be the major excitatory transmitter in the brain, generalized inhibition of a glutamate receptor subtype like the NMDAR causes side effects that clearly limit the potential for clinical applications. Both competitive NMDA and glycine antagonists, From: The Receptors: The Glutamate Receptors even though they are effective in preventing glutamate-mediated neurotoxicity, will cause generalized inhibition of NMDAR activities and thus have failed in many clinical trials. Open-channel block, a form of uncompetitive antagonism, is the most appealing strategy for therapeutic intervention during excessive NMDAR activation because this action of blockade; requires prior activation of the receptor. This property, in theory, leads to a higher degree of channel blockade in the presence of excessive levels of glutamate and little blockade at relatively lower levels, for example, during physiologic neurotransmission. As an alternative strategy, genetic manipulation of NR3 subunits can reduce glutamateinduced currents and Ca2+ influx through NMDARs without completely blocking their activation. Based on this molecular strategy of action, this chapter reviews the logical process that was applied over the last decade to develop memantine as the first clinically tolerated yet effective agent against NMDAR-mediated neurotoxicity. Phase 3 (final) clinical trials have shown that memantine is effective in treating moderateto- severe Alzheimer’s disease while being well tolerated. Memantine is also in trials for additional neurologic disorders, including other forms of dementia, glaucoma, and severe neuropathic pain. In addition, taking advantage of memantine’s preferential binding to open channels and the act that excessive NMDAR activity can be downregulated by S-nitrosylation, combinatorial drugs called NitroMemantine have recently been developed. These drugs use memantine as a homing signal to target NO to hyperactivated NMDARs to avoid systemic side effects of NO such as hypotension (low blood pressure). These second-generation memantine derivatives are designed as pathologically activated therapeutics, and in preliminary studies they appear to have even greater neuroprotective properties than memantine.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

references

  1. Lipton S, Rosenberg P. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 1994;330:613–622.

    Article  PubMed  CAS  Google Scholar 

  2. Lipton SA, Nicotera P. Calcium, free radicals and excitotoxins in neuronal apoptosis. Cell Calcium 1998;23:165–171.

    Article  PubMed  CAS  Google Scholar 

  3. Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov 2006;5:160–170.

    Article  PubMed  CAS  Google Scholar 

  4. Kemp JA, McKernan RM. NMDA receptor pathways as drug targets. Nat Neurosci 2002;5:1039–1042.

    Article  PubMed  CAS  Google Scholar 

  5. Wollmuth LP, Sobolevsky AI. Structure and gating of the glutamate receptor ion channel. Trends Neurosci 2004;27:321–328.

    Article  PubMed  CAS  Google Scholar 

  6. Zukin RS, Bennett MV. Alternatively spliced isoforms of the NMDARI receptor subunit. Trends Neurosci 1995;18:306–313.

    Article  PubMed  CAS  Google Scholar 

  7. Cull-Candy S, Brickley S, Farrant M. NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 2001;11:327–335.

    Article  PubMed  CAS  Google Scholar 

  8. Turetsky DM, Canzoniero LM, Sensi SL, et al. Cortical neurones exhibiting kainate-activated Co2+ uptake are selectively vulnerable to AMPA/kainate receptor-mediated toxicity. Neurobiol Dis 1994;1:101–110.

    Article  PubMed  CAS  Google Scholar 

  9. Aarts M, Iihara K, Wei WL, et al. A key role for TRPM7 channels in anoxic neuronal death. Cell 2003;115:863–177.

    Article  PubMed  CAS  Google Scholar 

  10. Xiong ZG, Zhu XM, Chu XP, et al. Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell 2004;118:687–198.

    Article  PubMed  CAS  Google Scholar 

  11. Gao J, Duan B, Wang DG, et al. Coupling between NMDA receptor and acid-sensing ion channel contributes to ischemic neuronal death. Neuron 2005;48:635–646.

    Article  PubMed  CAS  Google Scholar 

  12. Lucas DR, Newhouse JP. The toxic effect of sodium L-glutamate on the inner layers of the retina. AMA Arch Ophthalmol 1957;58:193–201.

    PubMed  CAS  Google Scholar 

  13. Olney JW. Glutamate-induced retinal degeneration in neonatal mice. Electron microscopy of the acutely evolving lesion. J Neuropathol Exp Neurol 1969;28:455–474.

    PubMed  CAS  Google Scholar 

  14. Olney JW, Ho OL. Brain damage in infant mice following oral intake of glutamate, aspartate or cysteine. Nature 1970;227:609–611.

    Article  PubMed  CAS  Google Scholar 

  15. Lipton SA. Molecular mechanisms of trauma-induced neuronal degeneration. Curr Opin Neurol Neurosurg 1993;6:588–596.

    PubMed  CAS  Google Scholar 

  16. Bonfoco E, Krainc D, Ankarcrona M, et al. Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-d-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc Natl Acad Sci USA 1995;92:7162–7166.

    Article  PubMed  CAS  Google Scholar 

  17. Quigley HA, Nickells RW, Kerrigan LA, et al. Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci 1995;36:774–786.

    PubMed  CAS  Google Scholar 

  18. Vorwerk CK, Lipton SA, Zurakowski D, et al. Chronic low-dose glutamate is toxic to retinal ganglion cells. Toxicity blocked by memantine. Invest Ophthalmol Vis Sci 1996;37:1618–1624.

    PubMed  CAS  Google Scholar 

  19. Naskar R, Vorwerk CK, Dreyer EB. Saving the nerve from glaucoma: memantine to caspaces. Semin Ophthalmol 1999;14:152–158.

    Article  PubMed  CAS  Google Scholar 

  20. Zeevalk GD, Nicklas WJ. Evidence that the loss of the voltage-dependent Mg2+ block at the N-methyl-d-aspartate receptor underlies receptor activation during inhibition of neuronal metabolism. J Neurochem 1992;59:1211–1220.

    Article  PubMed  CAS  Google Scholar 

  21. Mullins M, Sondheimer N, Huang Z. Spin-trapping NO in nNOS-deficient mice: indications for stroke therapy. In: Stamler JS GS, Moncada S, eds. The Biology of Nitric Oxide, Part 5. London: Portland Press; 1996:9.

    Google Scholar 

  22. Tovar KR, Westbrook GL. The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J Neurosci 1999;19:4180–4188.

    PubMed  CAS  Google Scholar 

  23. Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci 2002;5:405–414.

    PubMed  CAS  Google Scholar 

  24. Liu Y, Wong TP, Aarts M, et al. NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J Neurosci 2007;27:2846–2857.

    Article  PubMed  CAS  Google Scholar 

  25. Rogawski MA, Wenk GL. The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease. CNS Drug Rev 2003;9:275–308.

    Article  PubMed  CAS  Google Scholar 

  26. Selkoe DJ. Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 2001;81:741–766.

    PubMed  CAS  Google Scholar 

  27. Koh JY, Yang LL, Cotman CW. Beta-amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage. Brain Res 1990;533:315–320.

    Article  PubMed  CAS  Google Scholar 

  28. Mattson MP, Cheng B, Davis D, et al. beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J Neurosci 1992;12:376–389.

    PubMed  CAS  Google Scholar 

  29. Wu J, Anwyl R, Rowan MJ. beta-Amyloid-(1–40) increases long-term potentiation in rat hippocampus in vitro. Eur J Pharmacol 1995;284:R1–R3.

    Article  PubMed  CAS  Google Scholar 

  30. Topper R, Gehrmann J, Banati R, et al. Rapid appearance of beta-amyloid precursor protein immunoreactivity in glial cells following excitotoxic brain injury. Acta Neuropathol (Berl) 1995;89:23–28.

    Article  CAS  Google Scholar 

  31. Harkany T, Abraham I, Timmerman W, et al. beta-Amyloid neurotoxicity is mediated by a glutamate-triggered excitotoxic cascade in rat nucleus basalis. Eur J Neurosci 2000;12:2735–2745.

    Article  PubMed  CAS  Google Scholar 

  32. Couratier P, Lesort M, Sindou P, et al. Modifications of neuronal phosphorylated tau immunoreactivity induced by NMDA toxicity. Mol Chem Neuropathol 1996;27:259–273.

    PubMed  CAS  Google Scholar 

  33. Simon RP, Swan JH, Griffiths T, et al. Blockade of N-methyl-d-aspartate receptors may protect against ischemic damage in the brain. Science 1984;226:850–852.

    Article  PubMed  CAS  Google Scholar 

  34. Balazs R, Hack N, Jorgensen OS, et al. N-Methyl-d-aspartate promotes the survival of cerebellar granule cells: pharmacological characterization. Neurosci Lett 1989;101:241–246.

    Article  PubMed  CAS  Google Scholar 

  35. Komuro H, Rakic P. Modulation of neuronal migration by NMDA receptors. Science 1993;260:95–97.

    Article  PubMed  CAS  Google Scholar 

  36. Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature 1993;361:31–39.

    Article  PubMed  CAS  Google Scholar 

  37. Cline HT, Debski EA, Constantine-Paton M. N-Methyl-d-aspartate receptor antagonist desegregates eye-specific stripes. Proc Natl Acad Sci USA 1987;84:4342–4345.

    Article  PubMed  CAS  Google Scholar 

  38. Simon DK, Prusky GT, O’Leary DD, et al. N-Methyl-d-aspartate receptor antagonists disrupt the formation of a mammalian neural map. Proc Natl Acad Sci USA 1992;89:10593–10597.

    Article  PubMed  CAS  Google Scholar 

  39. Meldrum B, Garthwaite J. Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol Sci 1990;11:379–387.

    Article  PubMed  CAS  Google Scholar 

  40. Lipton SA. Prospects for clinically tolerated NMDA antagonists: open-channel blockers and alternative redox states of nitric oxide. Trends Neurosci 1993;16:527–532.

    Article  PubMed  CAS  Google Scholar 

  41. Nowak L, Bregestovski P, Ascher P, et al. Magnesium gates glutamate-activated channels in mouse central neurones. Nature 1984;307:462–465.

    Article  PubMed  CAS  Google Scholar 

  42. Mayer ML, Westbrook GL, Guthrie PB. Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 1984;309:261–263.

    Article  PubMed  CAS  Google Scholar 

  43. Dingledine R, Borges K, Bowie D, et al. The glutamate receptor ion channels. Pharmacol Rev 1999;51:7–61.

    PubMed  CAS  Google Scholar 

  44. Dawson VL, Dawson TM, London ED, et al. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc Natl Acad Sci USA 1991;88:6368–6371.

    Article  PubMed  CAS  Google Scholar 

  45. Dawson VL, Dawson TM, Bartley DA, et al. Mechanisms of nitric oxide–mediated neurotoxicity in primary brain cultures. J Neurosci 1993;13:2651–2661.

    PubMed  CAS  Google Scholar 

  46. Lipton SA, Choi YB, Pan ZH, et al. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 1993;364:626–632.

    Article  PubMed  CAS  Google Scholar 

  47. Yun HY, Gonzalez-Zulueta M, Dawson VL, et al. Nitric oxide mediates N-methyl-d-aspartate receptor-induced activation of p21ras. Proc Natl Acad Sci USA 1998;95:5773–5778.

    Article  PubMed  CAS  Google Scholar 

  48. Budd SL, Tenneti L, Lishnak T, et al. Mitochondrial and extramitochondrial apoptotic signaling pathways in cerebrocortical neurons. Proc Natl Acad Sci USA 2000;97:6161–6166.

    Article  PubMed  CAS  Google Scholar 

  49. Okamoto S, Li Z, Ju C, et al. Dominant-interfering forms of MEF2 generated by caspase cleavage contribute to NMDA-induced neuronal apoptosis. Proc Natl Acad Sci USA 2002;99:3974–3979.

    Article  PubMed  CAS  Google Scholar 

  50. Hara MR, Agrawal N, Kim SF, et al. S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nat Cell Biol 2005;7:665–674.

    Article  PubMed  CAS  Google Scholar 

  51. Beck C, Wollmuth LP, Seeburg PH, et al. NMDAR channel segments forming the extracellular vestibule inferred from the accessibility of substituted cysteines. Neuron 1999;22:559–570.

    Article  PubMed  CAS  Google Scholar 

  52. Wong EH, Kemp JA. Sites for antagonism on the N-methyl-d-aspartate receptor channel complex. Annu Rev Pharmacol Toxicol 1991;31:401–425.

    Article  PubMed  CAS  Google Scholar 

  53. Lipton SA, Choi Y-B, Takahashi H, et al. Cysteine regulation of protein function—as exemplified by NMDA-receptor modulation. Trends Neurosci 2002;25:474–480.

    Article  PubMed  CAS  Google Scholar 

  54. Takahashi H, Shin Y, Cho S-J, et al. Hypoxia enhances S-nitrosylation-mediated NMDA receptor inhibition via a thiol oxygen sensor motif. Neuron 2007;53:53–64.

    Article  PubMed  CAS  Google Scholar 

  55. Hickenbottom SL, Grotta J. Neuroprotective therapy. Semin Neurol 1998;18:485–492.

    Article  PubMed  CAS  Google Scholar 

  56. Lutsep HL, Clark WM. Neuroprotection in acute ischaemic stroke. Current status and future potential. Drugs R D 1999;1:3–8.

    Article  PubMed  CAS  Google Scholar 

  57. Palmer GC. Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies. Curr Drug Targets 2001;2:241–271.

    Article  PubMed  CAS  Google Scholar 

  58. Rang HP. Drugs and ionic channels: mechanisms and implications. Postgrad Med J 1981;57:89–97.

    PubMed  CAS  Google Scholar 

  59. Chen H-SV, Pellegrini JW, Aggarwal SK, et al. Open-channel block of N-methyl-d-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity. J Neurosci 1992;12:4427–4436.

    PubMed  CAS  Google Scholar 

  60. Chen H-SV, Wang YF, Rayudu PV, et al. Neuroprotective concentrations of the N-methyl-d-aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or long-term potentiation. Neuroscience 1998;86:1121–1132.

    Article  PubMed  CAS  Google Scholar 

  61. Chen H-SV, Lipton SA. Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells: uncompetitive antagonism. J Physiol 1997;499(Pt 1):27–46.

    PubMed  CAS  Google Scholar 

  62. Chen H-SV, Lipton SA. The chemical biology of clinically tolerated NMDA receptor antagonists. J Neurochem 2006;97:1611–1626.

    Article  PubMed  CAS  Google Scholar 

  63. Lei SZ, Pan ZH, Aggarwal SK, et al. Effect of nitric oxide production on the redox modulatory site of the NMDA receptor-channel complex. Neuron 1992;8:1087–1099.

    Article  PubMed  CAS  Google Scholar 

  64. Choi Y-B, Tenneti L, Le DA, et al. Molecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation. Nat Neurosci 2000;3:15–21.

    Article  PubMed  CAS  Google Scholar 

  65. Tominack RL, Hayden FG. Rimantadine hydrochloride and amantadine hydrochloride use in influenza A virus infections. Infect Dis Clin North Am 1987;1:459–478.

    PubMed  CAS  Google Scholar 

  66. Ditzler K. Efficacy and tolerability of memantine in patients with dementia syndrome. A double-blind, placebo controlled trial. Arzneimittelforschung 1991;41:773–780.

    PubMed  CAS  Google Scholar 

  67. Fleischhacker WW, Buchgeher A, Schubert H. Memantine in the treatment of senile dementia of the Alzheimer type. Prog Neuropsychopharmacol Biol Psychiatry 1986;10:87–93.

    Article  PubMed  CAS  Google Scholar 

  68. Bormann J. Memantine is a potent blocker of N-methyl-d-aspartate (NMDA) receptor channels. Eur J Pharmacol 1989;166:591–592.

    Article  PubMed  CAS  Google Scholar 

  69. Kornhuber J, Mack-Burkhardt F, Riederer P, et al. [3H]MK-801 binding sites in postmortem brain regions of schizophrenic patients. J Neural Transm 1989;77:231–236.

    Article  PubMed  CAS  Google Scholar 

  70. Chen H-S, Lipton SA. Pharmacological implications of two distinct mechanisms of interaction of memantine with N-methyl-d-aspartate–gated channels. J Pharmacol Exp Ther 2005;314:961–971. Epub 2005 May 18.

    Article  PubMed  CAS  Google Scholar 

  71. Wesemann W, Sturm G, Funfgeld EW. Distribution of metabolism of the potential anti-Parkinson drug memantine in the human. J Neural Transm Suppl 1980:143–148.

    Google Scholar 

  72. Rogawski MA. Low affinity channel blocking (uncompetitive) NMDA receptor antagonists as therapeutic agents—toward an understanding of their favorable tolerability. Amino Acids 2000;19:133–149.

    Article  PubMed  CAS  Google Scholar 

  73. Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003;348:1333–1341.

    Article  PubMed  CAS  Google Scholar 

  74. Tariot PN, Farlow MR, Grossberg GT, et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004;291:317–324.

    Article  PubMed  CAS  Google Scholar 

  75. Lipton SA. Turning down, but not off. Nature 2004;428:473.

    Article  PubMed  CAS  Google Scholar 

  76. Kashiwagi K, Masuko T, Nguyen CD, et al. Channel blockers acting at N-methyl-d-aspartate receptors: differential effects of mutations in the vestibule and ion channel pore. Mol Pharmacol 2002;61:533–545.

    Article  PubMed  CAS  Google Scholar 

  77. Danysz W, Parsons CG. The NMDA receptor antagonist memantine as a symptomatological and neuroprotective treatment for Alzheimer’s disease: preclinical evidence. Int J Geriatr Psychiatry 2003;18:S23–S32.

    Article  PubMed  Google Scholar 

  78. Wollmuth LP, Kuner T, Sakmann B. Adjacent asparagines in the NR2-subunit of the NMDA receptor channel control the voltage-dependent block by extracellular Mg2+. J Physiol 1998;506:13–32.

    Article  PubMed  CAS  Google Scholar 

  79. Wollmuth LP, Kuner T, Sakmann B. Intracellular Mg2+ interacts with structural determinants of the narrow constriction contributed by the NR1-subunit in the NMDA receptor channel. J Physiol 1998;506:33–52.

    Article  PubMed  CAS  Google Scholar 

  80. Bresink I, Benke TA, Collett VJ, et al. Effects of memantine on recombinant rat NMDA receptors expressed in HEK 293 cells. Br J Pharmacol 1996;119:195–204.

    PubMed  CAS  Google Scholar 

  81. Antonov SM, Johnson JW. Voltage-dependent interaction of open-channel blocking molecules with gating of NMDA receptors in rat cortical neurons. J Physiol 1996;493:425–445.

    PubMed  CAS  Google Scholar 

  82. Blanpied TA, Boeckman FA, Aizenman E, et al. Trapping channel block of NMDA-activated responses by amantadine and memantine. J Neurophysiol 1997;77:309–323.

    PubMed  CAS  Google Scholar 

  83. Sobolevsky AI, Koshelev SG, Khodorov BI. Interaction of memantine and amantadine with agonist-unbound NMDA-receptor channels in acutely isolated rat hippocampal neurons. J Physiol 1998;512:47–60.

    Article  PubMed  CAS  Google Scholar 

  84. Mealing GA, Lanthorn TH, Small DL, et al. Structural modifications to an N-methyl-d-aspartate receptor antagonist result in large differences in trapping block. J Pharmacol Exp Ther 2001;297:906–914.

    PubMed  CAS  Google Scholar 

  85. Bolshakov KV, Gmiro VE, Tikhonov DB, et al. Determinants of trapping block of N-methyl-d-aspartate receptor channels. J Neurochem 2003;87:56–65.

    Article  PubMed  CAS  Google Scholar 

  86. Masuo K, Enomoto K, Maeno T. Effects of memantine on the frog neuromuscular junction. Eur J Pharmacol 1986;130:187–195.

    Article  PubMed  CAS  Google Scholar 

  87. Lampe H, Bigalke H. Modulation of glycine-activated membrane current by adamantane derivatives. Neuroreport 1991;2:373–376.

    Article  PubMed  CAS  Google Scholar 

  88. Netzer R, Bigalke H. Memantine reduces repetitive action potential firing in spinal cord nerve cell cultures. Eur J Pharmacol 1990;186:149–155.

    Article  PubMed  CAS  Google Scholar 

  89. Osborne NN, Beale R, Golombiowska-Nikitin K, et al. The effect of memantine on various neurobiological processes. Arzneimittelforschung 1982;32:1246–1255.

    PubMed  CAS  Google Scholar 

  90. Wesemann W, Sontag KH, Maj J. Pharmacodynamics and pharmacokinetics of memantine [in German]. Arzneimittelforschung 1983;33:1122–1134.

    PubMed  CAS  Google Scholar 

  91. Rammes G, Rupprecht R, Ferrari U, et al. The N-methyl-d-aspartate receptor channel blockers memantine, MRZ 2/579 and other amino-alkyl-cyclohexanes antagonise 5-HT(3) receptor currents in cultured HEK-293 and N1E-115 cell systems in a non-competitive manner. Neurosci Lett 2001;306:81–84.

    Article  PubMed  CAS  Google Scholar 

  92. Reiser G, Binmoller FJ, Koch R. Memantine (1-amino-3,5-dimethyladamantane) blocks the serotonin-induced depolarization response in a neuronal cell line. Brain Res 1988;443:338–344.

    Article  PubMed  CAS  Google Scholar 

  93. Maskell PD, Speder P, Newberry NR, et al. Inhibition of human alpha 7 nicotinic acetylcholine receptors by open channel blockers of N-methyl-d-aspartate receptors. Br J Pharmacol 2003;140:1313–1319.

    Article  PubMed  CAS  Google Scholar 

  94. Aracava Y, Pereira EF, Maelicke A, et al. Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than N-methyl-d-aspartate receptors in rat hippocampal neurons. J Pharmacol Exp Ther 2005;312:1195–1205. Epub 2004 November 2.

    Article  PubMed  CAS  Google Scholar 

  95. Banerjee P, Samoriski G, Gupta S. Comments on “Memantine blocks alpha7* nicotinic acetylcholine receptors more potently than N-methyl-d-aspartate receptors in rat hippocampal neurons”. J Pharmacol Exp Ther 2005;313:928–9; author reply, 30–33.

    Article  PubMed  CAS  Google Scholar 

  96. Miguel-Hidalgo JJ, Alvarez XA, Cacabelos R, et al. Neuroprotection by memantine against neurodegeneration induced by beta-amyloid(1–40). Brain Res 2002;958:210–221.

    Article  PubMed  CAS  Google Scholar 

  97. Tanila H, Minkevicine R, Banjeree P. Behavioral effects of subchronic memantine treatment in APP/PS1 double mutant mice modeling Alzheimer’s disease. J Neurochem 2003;85(Suppl 1):42.

    Google Scholar 

  98. Iqbal K, Li L, Sengupta A, et al. Memantine restores okadaic acid-induced changes in protein phosphatase-2A., CAMKII and tau hyperphosphorylation in rat. J Neurochem 2003;85(Suppl 1):42.

    Google Scholar 

  99. Parsons CG, Danysz W, Quack G. Memantine is a clinically well tolerated N-methyl-d-aspartate (NMDA) receptor antagonist—a review of preclinical data. Neuropharmacology 1999;38:735–767.

    Article  PubMed  CAS  Google Scholar 

  100. Osborne NN. Memantine reduces alterations to the mammalian retina, in situ, induced by ischemia. Vis Neurosci 1999;16:45–52.

    Article  PubMed  CAS  Google Scholar 

  101. Winblad B, Poritis N. Memantine in severe dementia: results of the 9M-Best Study (Benefit and Efficacy in Severely Demented Patients During Treatment with Memantine). Int J Geriatr Psychiatry 1999;14:135–146.

    Article  PubMed  CAS  Google Scholar 

  102. Orgogozo JM, Rigaud AS, Stoffler A, et al. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke 2002;33:1834–1839.

    Article  PubMed  CAS  Google Scholar 

  103. Lipton SA, Wang YF. NO-related species can protect from focal cerebral ischemia/reperfusion. In: Krieglstein J, Oberpichler-Schwenk H, eds. Pharmacology of Cerebral Ischemia. Stuttgart: Wissenschaftliche Verlagsgesellschaft; 1996:183–191.

    Google Scholar 

  104. Zurakowski D, Vorwerk CK, Gorla M, et al. Nitrate therapy may retard glaucomatous optic neuropathy, perhaps through modulation of glutamate receptors. Vision Res 1998;38:1489–1494.

    Article  PubMed  CAS  Google Scholar 

  105. Ciabarra AM, Sullivan JM, Gahn LG, et al. Cloning and characterization of chi-1: a developmentally regulated member of a novel class of the ionotropic glutamate receptor family. J Neurosci 1995;15:6498–6508.

    PubMed  CAS  Google Scholar 

  106. Sucher NJ, Akbarian S, Chi CL, et al. Developmental and regional expression pattern of a novel NMDA receptor-like subunit (NMDAR-L) in the rodent brain. J Neurosci 1995;15:6509–6520.

    PubMed  CAS  Google Scholar 

  107. Andersson O, Stenqvist A, Attersand A, et al. Nucleotide sequence, genomic organization, and chromosomal localization of genes encoding the human NMDA receptor subunits NR3A and NR3B. Genomics 2001;78:178–184.

    Article  PubMed  CAS  Google Scholar 

  108. Nishi M, Hinds H, Lu HP, et al. Motoneuron-specific expression of NR3B, a novel NMDA-type glutamate receptor subunit that works in a dominant-negative manner. J Neurosci 2001;21:RC185.

    PubMed  CAS  Google Scholar 

  109. Chatterton JE, Awobuluyi M, Premkumar LS, et al. Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 2002;415:793–798.

    PubMed  CAS  Google Scholar 

  110. Matsuda K, Kamiya Y, Matsuda S, et al. Cloning and characterization of a novel NMDA receptor subunit NR3B: a dominant subunit that reduces calcium permeability. Brain Res Mol Brain Res 2002;100:43–52.

    Article  PubMed  CAS  Google Scholar 

  111. Meguro H, Mori H, Araki K, et al. Functional characterization of a heteromeric NMDA receptor channel expressed from cloned cDNAs. Nature 1992;357:70–74.

    Article  PubMed  CAS  Google Scholar 

  112. Monyer H, Sprengel R, Schoepfer R, et al. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 1992;256:1217–1221.

    Article  PubMed  CAS  Google Scholar 

  113. Das S, Sasaki YF, Rothe T, et al. Increased NMDA current and spine density in mice lacking the NMDA receptor subunit NR3A. Nature 1998;393:377–381.

    Article  PubMed  CAS  Google Scholar 

  114. Perez-Otano I, Schulteis CT, Contractor A, et al. Assembly with the NR1 subunit is required for surface expression of NR3A-containing NMDA receptors. J Neurosci 2001;21:1228–1237.

    PubMed  CAS  Google Scholar 

  115. Sasaki YF, Rothe T, Premkumar LS, et al. Characterization and comparison of the NR3A subunit of the NMDA receptor in recombinant systems and primary cortical neurons. J Neurophysiol 2002;87:2052–2063.

    PubMed  CAS  Google Scholar 

  116. Matsuda K, Fletcher M, Kamiya Y, et al. Specific assembly with the NMDA receptor 3B subunit controls surface expression and calcium permeability of NMDA receptors. J Neurosci 2003;23:10064–10073.

    PubMed  CAS  Google Scholar 

  117. Yao Y, Mayer ML, Characterization of a soluble ligand binding domain of the NMDA receptor regularly subunit NR3A. J Neurosci 2006;26:4559–4566.

    Article  PubMed  CAS  Google Scholar 

  118. Awobuluyi M, Yang J, Ye Y, et al. Subunit-specific roles of glycine-binding domains in activation of NR1/NR3 N-methyl-d-aspartate receptors. Mol Pharmacol 2007;71:112–122. Epub 2006 Oct 17.

    Article  PubMed  CAS  Google Scholar 

  119. Wada A, Takahashi H, Lipton SA, et al. NR3A modulates the outer vestibule of the “NMDA” receptor channel. J Neurosci 2006;26:13156–13166.

    Article  PubMed  CAS  Google Scholar 

  120. Lees KR, Asplund K, Carolei A, et al. Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial. GAIN International Investigators. Lancet 2000;355:1949–154.

    Article  PubMed  CAS  Google Scholar 

  121. Sacco RL, DeRosa JT, Haley EC Jr, et al. Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial. JAMA 2001;285:1719–1728.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. Huei-Sheng Vincent Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dongxian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stuart A. Lipton
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Anesthesiology and Biological Chemistry Department of Anatomy and Neurobiology, Washington University Pain Center Washington University School of Medicine, St. Louis, MO

    Robert W. Gereau PhD

  2. Department of Molecular Pharmacology and Biological Chemistry, Northwestern University Feinberg School of Medicine, Chicago, IL

    Geoffrey T. Swanson PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2008 Humana Press

About this chapter

Cite this chapter

Vincent Chen, HS., Zhang, D., Lipton, S.A. (2008). Clinically Tolerated Strategies for NMDA Receptor Antagonism. In: Gereau, R.W., Swanson, G.T. (eds) The Glutamate Receptors. The Receptors. Humana Press. https://doi.org/10.1007/978-1-59745-055-3_8

Download citation

Publish with us

Policies and ethics

Search

Navigation