Movatterモバイル変換

[0]ホーム
URL:

Skip to main content

Advertisement

Springer Nature Link
Log in

Failures and successes of NMDA receptor antagonists: Molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults

  • Published:
NeuroRX

Summary

Excitotoxicity, defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, has been implicated as one of the key factors contributing to neuronal injury and death in a wide range of both acute and chronic neurologic disorders. Excitotoxic cell death is due, at least in part, to excessive activation ofN-methyl-d-aspartate (NMDA)-type glutamate receptors and hence excessive Ca2+ influx through the receptor’s associated ion channel. Physiological NMDA receptor activity, however, is also essential for normal neuronal function; potential neuroprotective agents that block virtually all NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of diseases including stroke and neurodegenerative disorders such as Huntington’s disease. In contrast, studies in my laboratory were the first to show that memantine, an adamantane derivative, preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission. Past clinical use for other indications has demonstrated that memantine is well tolerated, and it has recently been approved in both Europe and the USA for the treatment of dementia of the Alzheimer’s type. Clinical studies of the safety and efficacy of memantine for other neurological disorders, including glaucoma and other forms of dementia, are currently underway. A series of second-generation memantine derivatives are currently in development and may prove to have even greater neuroprotective properties than does memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites, in addition to its ion channel, that could potentially be used for safe but effective clinical intervention.

Article PDF

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

References

  1. Lipton SA, Rosenberg RA. Mechanisms of disease: excitatory amino acids as a final common pathway in neurologic disorders.N Engl J Med 30: 613–622, 1994.

    Google Scholar 

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

    Article PubMed CAS  Google Scholar 

  3. Kemp JA, McKernan RM. NMDA receptor pathways as drug targets.Nature Neurosci 5[Suppl]: 1039–1042, 2002.

    Article PubMed CAS  Google Scholar 

  4. Kemp JA, Kew JN, Gill R. Handbook of experimental pharmacology, Vol 141 (Jonas P, Monyer H, eds), pp 495–527. Berlin: Springer, 1999.

    Google Scholar 

  5. Lees KR, Asplund K, Carolei A, Davis SM, Diener HC, Kaste M et al. Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomized controlled trial. GAIN International Investigators.Lancet 355: 1949–1954, 2000.

    Article PubMed CAS  Google Scholar 

  6. Sacco RL, DeRosa JT, Haley EC Jr, Levin B, Ordronneau P, Phillips SJ et al. Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial.JAMA 28: 1719–1728, 2001.

    Article  Google Scholar 

  7. Seif el Nasr M, Peruche B, Rossberg C, Mennel HD, Krieglstein J. Neuroprotective effect of memantine demonstrated in vivo and in vitro.Eur J Pharmacol 185: 19–24, 1990.

    Article PubMed CAS  Google Scholar 

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

    Article PubMed CAS  Google Scholar 

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

    CAS  Google Scholar 

  10. Chen HS, Pellegrini JW, Aggarwal SK, Lei SZ, Warach S, Jensen FE et al. Open-channel block of NMDA responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity.J Neurosci 12: 4427–4436, 1992.

    PubMed CAS  Google Scholar 

  11. Chen HS, Wang YF, Rayudu PV, Edgecomb P, Neill JC, Segal MM et al. Neuroprotective concentration of the NMDA open-channel blocker memantine are effective without cytoplasmic vacuolization following post-ischemic administration and do not block maze learning or LTP.Neuroscience 86: 1121–1132, 1998.

    Article PubMed CAS  Google Scholar 

  12. Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ. Memantine in moderate-to-severe Alzheimer’s disease.N Engl J Med 348: 1333–1341, 2003.

    Article PubMed CAS  Google Scholar 

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

    Article PubMed CAS  Google Scholar 

  14. Lucas DR, Newhouse JP. The toxic effect of sodiuml-glutamate on the inner layers of the retina.Am Med Assoc Arch Ophthalmol 58: 193–201, 1957.

    CAS  Google Scholar 

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

    Article PubMed CAS  Google Scholar 

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

    Article PubMed CAS  Google Scholar 

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

    PubMed CAS  Google Scholar 

  18. Bonfoco E, Krainc D, Ankarcrona M, Nicotera P, Lipton SA. Apoptosis and necrosis: two distinct events induced respectively by mild and intense insults with NMDA or nitric oxide/superoxide in cortical cell cultures.Proc Natl Acad Sci USA 92: 7162–7166, 1995.

    Article PubMed CAS  Google Scholar 

  19. Dreyer EB, Zhang D, Lipton SA. Transcriptional or translational inhibition blocks low dose NMDA-mediated cell death.Neuroreport 6: 942–944, 1995.

    Article PubMed CAS  Google Scholar 

  20. Quigley HA, Nickells RW, Kerrigan LA, Pease ME, Thibault DJ, Zack DJ. Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis.Invest Ophthalmol Vis Sci 36: 774–786, 1995.

    PubMed CAS  Google Scholar 

  21. Vorwerk CK, Lipton SA, Zurakowski D, Hyman BT, Sabel BA, Dreyer EB. Chronic low dose glutamate is toxic to retinal ganglion cells: toxicity blocked by memantine.Invest Ophthalmol Vis Sci 37: 1618–1624, 1996.

    PubMed CAS  Google Scholar 

  22. Dreyer EB, Grosskreutz CL. Excitatory mechanisms in retinal ganglion cell death in primary open angle glaucoma (POAG).Clin Neurosci 4: 270–273, 1997.

    PubMed CAS  Google Scholar 

  23. Dreyer EB, Lipton SA. New perspectives on glaucoma.JAMA 281: 306–308, 1999.

    Article PubMed CAS  Google Scholar 

  24. Naskar R, Vorwerk CK, Dreyer EB. Saving the nerve from glaucoma: memantine to caspases.Semin Ophthalmol 4: 152–158, 1999.

    Article  Google Scholar 

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

    Google Scholar 

  26. Dawson VL, Dawson TM, London ED, Bredt DS, Snyder SH. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures.Proc Natl Acad Sci USA 88: 6368–6371, 1991.

    Article PubMed CAS  Google Scholar 

  27. Dawson VL, Dawson TM, Bartley DA, Uhl GR, Snyder SH. Mechanisms of nitric oxide-mediated neurotoxicity in primary brain cultures.J Neurosci 13: 2651–2661, 1993.

    PubMed CAS  Google Scholar 

  28. Lipton SA, Choi Y-B, Pan Z-H, Lei SZ, Chen H-SV, Sucher NJ, Singel DJ, Loscalzo J, Stamler JS. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds.Nature 364: 626–632, 1993.

    Article PubMed CAS  Google Scholar 

  29. Tenneti L, D’Emilia DM, Troy CM, Lipton SA. Role of caspases inN-methyl-d-aspartate-induced apoptosis in cerebrocortical neurons.J Neurochem 71: 946–959, 1998.

    Article PubMed CAS  Google Scholar 

  30. 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 95: 5773–5778, 1998.

    Article PubMed CAS  Google Scholar 

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

    Article PubMed CAS  Google Scholar 

  32. Okamoto S-I, Li Z, Ju C, Schölzke MN, Matthews E, Cui J, Salvesen GS, Bossy-Wetzel E, Lipton SA. Dominant-interfering forms of MEF2 generated by caspase cleavage contribute to NMDA-induced neuronal apoptosis.Proc Natl Acad Sci USA 99: 3974–3979, 2002.

    Article PubMed CAS  Google Scholar 

  33. Johnson J, Ascher P. Glycine potentiates the NMDA response in cultured mouse brain neurons.Nature 325: 529–531, 1987.

    Article PubMed CAS  Google Scholar 

  34. McBain CJ, Mayer ML. N-methyl-d-aspartic acid receptor structure and function.Physiol Rev 74: 723–760, 1994.

    PubMed CAS  Google Scholar 

  35. Lipton SA, Choi Y-B, Takahashi T, Zhang D, Li W, Godzik A, Bankston LA. Cysteine regulation of protein function—as exemplified by NMDA-receptor modulation.Trends Neurosci 25: 474–490, 2002.

    Article PubMed CAS  Google Scholar 

  36. Koroshetz WJ, Moskowitz MA. Emerging treatments for stroke in humans.Trends Pharmacol Sci 17: 227–233, 1996.

    Article PubMed CAS  Google Scholar 

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

    Article PubMed CAS  Google Scholar 

  38. Lutsep HL, Clark WM. Neuroprotection in acute ischaemic stroke: current status and future potential.Drug Res Dev 1: 3–8, 1999.

    Article CAS  Google Scholar 

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

    Article PubMed CAS  Google Scholar 

  40. Palmer GC. Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies.Curr Drug Targ 2: 241–271, 2001.

    Article CAS  Google Scholar 

  41. Chen H-SV, Rastogi, Lipton SA. Q/R/N site mutations in the M2 region of NMDAR1/NMDAR2A receptors reveal a non-specific site for memantine action.Soc Neurosci Abstr 24: 342, 1998.

    Google Scholar 

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

    Article PubMed CAS  Google Scholar 

  43. 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 38: 735–767, 1999.

    Article PubMed CAS  Google Scholar 

  44. Lipton SA. Memantine prevents HIV coat protein-induced neuronal injury in vitro.Neurology 42: 1403–1405, 1992.

    PubMed CAS  Google Scholar 

  45. Pellegrini JW, Lipton SA. Delayed administration of memantine prevents NMDA receptor-mediated neurotoxicity.Ann Neurol 33: 403–407, 1993.

    Article PubMed CAS  Google Scholar 

  46. Sucher NJ, Lipton SA, Dreyer EB. Molecular basis of glutamate toxicity in retinal ganglion cells.Vision Res 37: 3483–3493, 1997.

    Article PubMed CAS  Google Scholar 

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

    Article PubMed CAS  Google Scholar 

  48. 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 Geriat Psych 14: 135–146, 1999.

    Article CAS  Google Scholar 

  49. Lipton SA, Wang YF. NO-related species can protect from focal cerebral ischemia/reperfusion. In:Pharmacology of cerebral ischemia (Krieglstein J, Oberpichler-Schwenk H, eds), pp 183–191. Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH, 1996.

    Google Scholar 

  50. Zurakowski D, Vorwerk CK, Gorla M, Kanellopoulos AJ, Chaturvedi N, Grosskreutz CL et al. Nitrate therapy may retard glaucomatous optic neuropathy, perhaps through modulation of glutamate receptors.Vision Res 38: 1489–1494, 1998.

    Article PubMed CAS  Google Scholar 

  51. Lipton SA, Rayudu, PV, Choi Y-B, Sucher NJ, Chen HSV. Redox modulation of the NMDA receptor by NO-related species. In:Progress in brain research, Vol 118 (Mize RR, Dawson V, Dawson TM, Friedlander M, eds), pp 73–82. Amsterdam: Elsevier, 1998.

    Google Scholar 

  52. Choi Y-B, Tenneti L, Le DA, Ortiz J, Bai G, Chen H-SV, Lipton SA. Molecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation.Nature Neurosci 3: 15–21, 2000.

    Article PubMed CAS  Google Scholar 

  53. Ankarcrona M, Dypbukt JM, Bonfoco E, Zhivotovsky B, Orrenius S, Lipton SA, Nicotera P. Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial integrity.Neuron 15: 961–973, 1995.

    Article PubMed CAS  Google Scholar 

  54. Le DA, Lipton SA. Potential and current use ofN-methyl-d-aspartate (NMDA) receptor antagonists in diseases of aging.Drugs Aging 18: 717–724, 2001.

    Article PubMed CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Burnham Institute, University of California, 92037, San Diego, La Jolla, California

    Stuart A. Lipton

  2. The Salk Institute for Biological Studies, University of California, 92037, San Diego, La Jolla, California

    Stuart A. Lipton

  3. The Scripps Research Institute, University of California, 92037, San Diego, La Jolla, California

    Stuart A. Lipton

  4. 10901 North Torrey Pines Road, 92037, La Jolla, CA

    Stuart A. Lipton

Authors
  1. Stuart A. Lipton

Corresponding author

Correspondence toStuart A. Lipton.

Rights and permissions

About this article

Cite this article

Lipton, S.A. Failures and successes of NMDA receptor antagonists: Molecular basis for the use of open-channel blockers like memantine in the treatment of acute and chronic neurologic insults.Neurotherapeutics1, 101–110 (2004). https://doi.org/10.1602/neurorx.1.1.101

Download citation

Key Words

Advertisement

[8]ページ先頭
©2009-2026 Movatter.jp