Skip to main content
PMC home page
American Journal of Alzheimer's Disease and Other Dementias logoLink to American Journal of Alzheimer's Disease and Other Dementias
. 2004 Sep-Oct;19(5):269–274. doi: 10.1177/153331750401900502

Why do many NMDA antagonists fail, while others are safe and effective at blocking excitotoxicity associated with dementia and acute injury?

Benedict C Albensi 1, Chiazor Igoechi 2, Damir Janigro 3, Erin Ilkanich 4
PMCID: PMC10833778  PMID: 15553982

Abstract

Similar to drug development programs for stroke and traumatic brain injury, programs developed for Alzheimer's disease (AD) have not been very effective in treating dementia. Recently, researchers have explored modulating excitatory synaptic neurotransmission via the N-methyl-D-aspartate receptor (NMDAR) to treat AD. However, many investigators doubt that NMDA antagonists are safe and effective for treating persons with AD because they have failed in stroke and trauma programs. This article explores the role of NMDA-mediated excitotoxicity in AD, reviews how the NMDAR functions, highlights the side effects and alternate signaling pathways that are initiated from NMDAR activation, provides examples of NMDA antagonists that do not exhibit the typical side effects, and discusses why some NMDA antagonist compounds are effective and safe in limiting cascades of excitotoxicity in dementia or acute brain injury.

Keywords: dementia, brain injury, NMDA antagonist, NMDAR, Alzheimer's disease, excitotoxicity

Full Text

The Full Text of this article is available as a PDF (138.0 KB).

Contributor Information

Benedict C. Albensi, Center for Cerebrovascular Research, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University; Department of Biology, Case Western Reserve University, Cleveland, Ohio.

Chiazor Igoechi, Department of Biology, Case Western Reserve University, Cleveland, Ohio.

Damir Janigro, Center for Cerebrovascular Research, Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University.

Erin Ilkanich, Department of Biology, Case Western Reserve University, Cleveland, Ohio.

References

  1. Ikonomidou C, Turski L: Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury? Lancet Neurol. 2002; 1(6): 383-386. [DOI] [PubMed] [Google Scholar]
  2. Roesler R, Quevedo J, Schroder N: Is it time to conclude that NMDA antagonists have failed? Lancet Neurol.2003; 2(1): 13-13. [DOI] [PubMed] [Google Scholar]
  3. Smith PF: Therapeutic N-methyl-D-aspartate receptor antagonists: Will reality meet expectation? Curr Opin Investig Drugs.2003; 4(7): 826-832. [PubMed] [Google Scholar]
  4. Scarpini E, Scheltens P, Feldman H: Treatment of Alzheimer's disease: Current status and new perspectives. Lancet Neurol.2003; 2(9): 539-547. [DOI] [PubMed] [Google Scholar]
  5. van Reekum R, Black SE, Conn D, et al.: Cognition-enhancing drugs in dementia: A guide to the near future. Can J Psychiatry.1997; 42(Suppl 1): 35S-50S. [PubMed] [Google Scholar]
  6. Mondadori C: Nootropics: Preclinical results in the light of clinical effects; Comparison with tacrine. Crit Rev Neurobiol.1996; 10(3-4): 357-370. [DOI] [PubMed] [Google Scholar]
  7. Mayeux R, Sano M: Treatment of Alzheimer's disease. N Engl J Med.1999; 341(22): 1670-1679. [DOI] [PubMed] [Google Scholar]
  8. Mattson MP, Furukawa K, Bruce AJ, et al.: Calcium homeostasis and free radical metabolism as convergence points in the pathophysiology of dementia. In Wasco W, Tanzi RE: Molecular Mechanisms of Dementia. Totowa, NJ: Humana Press, 1997. [Google Scholar]
  9. Rogawski MA, Wenk GL: The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease. CNS Drug Rev. 2003; 9(3): 275-308. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Muller WE, Mutschler E, Riederer P: Noncompetitive NMDA receptor antagonists with fast open-channel blocking kinetics and strong voltage-dependency as potential therapeutic agents for Alzheimer's dementia. Pharmacopsychiatry.1995; 28(4): 113-124. [DOI] [PubMed] [Google Scholar]
  11. Masliah E, Raber J, Alford M, et al.: Amyloid protein precursor stimulates excitatory amino acid transport. J Biol Chem.1998; 273(20): 12548-12554. [DOI] [PubMed] [Google Scholar]
  12. Yamada KA: Modulating excitatory synaptic neurotransmission: Potential treatment for neurological disease? Neurobiol Dis.1998; 5(2): 67-80. [DOI] [PubMed] [Google Scholar]
  13. Watkins SC: The NMDA concept: Origins and developments. In Collingbridge GL, Watkins JC (eds.): The NMDA Receptor. Second Edition.Oxford: Oxford University Press, 1994. [Google Scholar]
  14. Yun L, Zhang J: Recent development in NMDA receptors. Chin Med J.2000; 113(10): 948-956. [PubMed] [Google Scholar]
  15. Craig AM, Blackstone CD, Huganir RL, et al.: Selective clustering of glutamate and gamma-aminobutyric acid receptors opposite terminals releasing the corresponding neurotransmitters. Proc Natl Acad Sci USA.1994; 91(26): 12373-12377. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Dodt HU, Frick A, Kampe K, et al.: NMDA and AMPA receptors on neocortical neurons are differentially distributed. Eur J Neurosci. 1998; 10(11): 3351-3357. [DOI] [PubMed] [Google Scholar]
  17. Sattler R, Xiong Z, Lu W, et al.: Distinct roles of synaptic and extrasynaptic NMDA receptors in excitotoxicity. J Neurosci.2000; 20(1): 22-33. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. McIlhinney RA, Philipps E, Le Bourdelles B, et al.: Assembly of N-methyl-D-aspartate (NMDA) receptors. Biochem Soc Trans.2003; 31(Pt 4): 865-868. [DOI] [PubMed] [Google Scholar]
  19. Flint AC, Maisch US, Weishaupt JH, et al.: NR2A subunit expression shortens NMDA receptor synaptic currents in developing neocortex. J Neurosci.1997; 17(7): 2469-2476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Cull-Candy S, Brickley S, Farrant M: NMDA receptor subunits: Diversity, development and disease. Curr Opin Neurobiol.2001; 11(3): 327-335. [DOI] [PubMed] [Google Scholar]
  21. Wild GC, Benzel EC: Essentals of Neurochemistry. Boston, London: Jones and Bartlett Publishers, 1994. [Google Scholar]
  22. Petrenko AB, Yamakura T, Baba H, et al.: The Role of N-methyld-Aspartate (NMDA) receptors in pain: A review. Anasth Analg. 2003; 97(4): 1108-1116. [DOI] [PubMed] [Google Scholar]
  23. Prybylowski K, Wenthold RJ: N-Methyl-D-aspartate receptors: Subunit assembly and trafficking to the synapse. J Biol Chem.2004; 279(11): 9673-9676. [DOI] [PubMed] [Google Scholar]
  24. Collingridge GL, Watkins JC: The NMDA Receptor.Oxford, New York, Tokyo: Oxford University Press, 1994. [Google Scholar]
  25. Hardingham GE, Bading H: The Yin and Yang of NMDA receptor signaling. Trends Neurosci.2003; 26(2): 81-89. [DOI] [PubMed] [Google Scholar]
  26. Haberny KA, Paule MG, Scallet AC, et al.: Ontogeny of the Nmethyl-D-aspartate (NMDA) receptor system and susceptibility to neurotoxicity. Toxicol Sci.2002; 68(1): 9-17. [DOI] [PubMed] [Google Scholar]
  27. Deutsch SI, Mastropaolo J, Rosse RB: Neurodevelopmental consequences of early exposure to phencyclidine and related drugs. Clin Neuropharmacol.1998; 21(6): 320-322. [PubMed] [Google Scholar]
  28. Klitgaard H, Matagne A, Lamberty Y: Use of epileptic animals for adverse effect testing. Epilepsy Res.2002; 50(1-2): 55-65. [DOI] [PubMed] [Google Scholar]
  29. Ikonomidou C, Bosch F, Miksa M, et al.: Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science.1999; 283(5398): 70-74. [DOI] [PubMed] [Google Scholar]
  30. Hlinak Z, Krejci I: MK-801 induced amnesia for the elevated plus-maze in mice. Behav Brain Res.2002; 131(1-2): 221-225. [DOI] [PubMed] [Google Scholar]
  31. Sharp FR, Tomitaka M, Bernaudin M, et al.: Psychosis: Pathological activation of limbic thalamocortical circuits by psychomimetics and schizophrenia? Trends Neurosci.2001; 24(6): 330-334. [DOI] [PubMed] [Google Scholar]
  32. Albensi BC, Alasti N, Mueller AL: Long-term potentiation in the presence of NMDA receptor antagonist arylalkylamine spider toxins. J Neurosci Res.2000; 62(2): 177-185. [DOI] [PubMed] [Google Scholar]
  33. Parks TN, Mueller AL, Artman LD, et al.: Arylamine toxins from funnel-web spider (Agelenopsis aperta) venom antagonize Nmethyl-D-aspartate receptor function in mammalian brain. J Biol Chem. 1991; 266(32): 21523-21529. [PubMed] [Google Scholar]
  34. Chazot PL: The NMDA receptor NR2B subunit: A valid therapeutic target for multiple CNS pathologies. Curr Med Chem.2004; 11: 389-396. [DOI] [PubMed] [Google Scholar]
  35. Chazot PL: CP-101606. Curr Opin Invest New Drugs. 2000; 1(3): 370-374. [PubMed] [Google Scholar]
  36. Nikam SS, Meltzer LT: NR2B selective NMDA receptor antagonists. Curr Pharm Design.8(10): 845-855. [DOI] [PubMed] [Google Scholar]
  37. Jarvis B, Figgitt DP: Memantine. Drugs Aging. 2003; 20(6): 465-476. [DOI] [PubMed] [Google Scholar]
  38. Reisberg B, Doody R, Stöffler A, et al.: Memantine in moderateto-severe Alzheimer's disease. N Engl J Med. 2003; 348(14): 1333-1341. [DOI] [PubMed] [Google Scholar]
  39. Feret B, Dicks R: Memantine. Formulary. 2004; 39: 91-103. [Google Scholar]

Articles from American Journal of Alzheimer's Disease and Other Dementias are provided here courtesy of SAGE Publications

RESOURCES