Skip to main content
NCBI home page
American Journal of Alzheimer's Disease and Other Dementias logoLink to American Journal of Alzheimer's Disease and Other Dementias
. 2005 Mar-Apr;20(2):77–85. doi: 10.1177/153331750502000206

Memantine: Targeting glutamate excitotoxicity in Alzheimer's disease and other dementias

José L Molinuevo, Albert Lladó, Lorena Rami 1
PMCID: PMC10833270  PMID: 15844753

Abstract

The management of dementia has changed since the development of new antidementia drugs. The benefits observed in Alzheimer's disease (AD) with selective cholinergic transmission treatments are mainly symptomatic, without clear evidence of neuroprotection. The hypothesis that glutamate-mediated neurotoxicity is involved in the pathogenesis of AD is finding increasingly more acceptance in the scientific community. Glutamate receptors are overactive, and N-methyl-Daspartate (NMDA) receptor antagonists have therapeutic potential for the treatment of AD and other neurological disorders. Memantine is a noncompetitive NMDA antagonist that is considered a neuroprotective drug. Memantine's capacity has been demonstrated in preclinical studies, and it is considered a useful symptomatic treatment for AD. Memantine has been shown to benefit cognition, function, and global outcome in patients with moderate to severe AD, and it is currently approved by the US Food and Drug Administration (FDA) for the treatment of moderate to severe AD. Recently, memantine has also demonstrated efficacy in the initial stages of AD, although FDA authorization is pending. This review highlights the important pharmacological and clinical aspects of memantine, as well as some basic mechanisms mediating glutamatergic neurodegeneration.

Keywords: memantine, Alzheimer’s disease, dementia, glutamate, N-methyl-D-aspartate receptor

Full Text

The Full Text of this article is available as a PDF (120.4 KB).

References

  1. Lobo A, Launer LJ, Fratiglioni L, et al.: Prevalence of dementia and major subtypes in Europe: A collaborative study of populationbased cohorts. Neurology Diseases in the Elderly Research Group. Neurology. 2000; 54 (11 suppl 5): S4-S9. [PubMed] [Google Scholar]
  2. Launer LJ, Hofman A: Frequency and impact of neurologic diseases in the elderly of Europe: A collaborative study of populationbased cohorts. Neurology. 2000; 54 (11 suppl 5): S1-S8. [PubMed] [Google Scholar]
  3. Hebert LE, Scherr PA, Bienias JL, et al.: Alzheimer disease in the US population. Prevalence estimates using the 2000 census. Arch Neurol. 2003; 60: 119-122. [DOI] [PubMed] [Google Scholar]
  4. Schenk D, Barbour R, Dunn W, et al.: Immunization with amyloidbeta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature. 1999; 400: 173-177. [DOI] [PubMed] [Google Scholar]
  5. Kilpatrick GJ, Tilbrook GS: Memantine. Curr Opin Investig Drugs. 2002; 3: 798-806. [PubMed] [Google Scholar]
  6. Mayeux R, Sano M: Treatment of Alzheimer's disease. N Engl J Med. 1999; 341: 1670-1679. [DOI] [PubMed] [Google Scholar]
  7. Winblad B, Möbius HJ, Stöfler A: Glutamate receptor as a target for Alzheimer's disease—are clinical results supporting the hope? J Neural Transm. 2002; 62(Suppl): 217-225. [DOI] [PubMed] [Google Scholar]
  8. Danysz W, Parsons CG, Bresink I, et al.: Glutamate in CNS disorders: A revived target for drug development? Drug News Perspect. 1995; 8: 261-277. [DOI] [PubMed] [Google Scholar]
  9. Müller WE, Mutschler E, Riederer P: Noncompetitive NMDA receptor antagonists with fast open channel kinetics and strong voltage dependency as potential therapeutic agents for Alzheimer's dementia. Pharmacopsychiatry. 1995; 28: 113-124. [DOI] [PubMed] [Google Scholar]
  10. Rothman SM, Olney JW: Excitotoxicity and the NMDA receptors. Trends Neurosci. 1987; 10: 299-302. [DOI] [PubMed] [Google Scholar]
  11. Rammsayer TH: Effects of pharmacologically induced changes in NMDA-receptor activity on long term memory in humans. Learn Mem. 2001; 8: 20-25. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Danysz W, Parsons CG, Möbius HG, et al.: Neuroprotection and symptomatological action of memantine relevant for Alzheimer's disease: A unified hypothesis on the mechanisms of action. Neurotox Res. 2000; 2: 85-98. [DOI] [PubMed] [Google Scholar]
  13. 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 (suppl 1): S23-S32. [DOI] [PubMed] [Google Scholar]
  14. Thompson RF, Kim JJ: Memory systems in the brain and localization of a memory. Proc Natl Acad Sci USA. 1996; 93 (24):13438-13444. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Baudry M, Davis JL: Long-Term Potentiation: A Debate of Current Issues. Cambridge, MA: MIT Press, 1991. [Google Scholar]
  16. Lynch G, Baudry M: The biochemistry of memory: A new and specific hypothesis. Science. 1984; 224(4653): 1057-1063. [DOI] [PubMed] [Google Scholar]
  17. Landfield PW, Deadwyler SA: Long-Term Potentiation: A Debate of Current Issues. Cambridge, MA: MIT Press, 1988. [Google Scholar]
  18. Baudry M, Thompson RF, Davis JL: Synaptic Plasticity, Molecular, Cellular, and Functional Aspects. Cambridge, MA: MIT Press, 1993. [Google Scholar]
  19. Masliah E, Mallory M, Aldford M, et al.: Caspase dependent DNA fragmentation might be associated with excititoxicity in Alzheimer's disease. J Neuropathol Exp Neurol. 1998; 57:1041-1052. [DOI] [PubMed] [Google Scholar]
  20. Li S, Mallory M, Aldford M, et al.: Glutamate transporter alteration in Alzheimer's disease are possibly associated with abnormal APP expression. J Neuropathol Exp Neurol. 1997; 56: 901-911. [DOI] [PubMed] [Google Scholar]
  21. Arias C, Arrieta I, Tapia R: Beta amyloid peptide fragment potentiates the calcium dependent release of excitatory amino acids from depolarized hippocampal slices. J Neurosci Res. 1995; 41: 561-566. [DOI] [PubMed] [Google Scholar]
  22. Wu JQ, Anwyl R, Rowan MJ: Beta amyloid selectively augments NMDA receptor-mediated synaptic transmission in rat hippocampus. NeuroReport. 1995; 6: 2409-2413. [DOI] [PubMed] [Google Scholar]
  23. Couratier P, Sindou P, Tabarud E, et al.: Modulation of tau neuronal expression induced by NMDA, non-NMDA and metabotropic glutamate receptor agonists. Neurodegeneration. 1995; 4: 33-41. [DOI] [PubMed] [Google Scholar]
  24. Sze C, Bi H, Kleinschmidt-DeMasters BK, et al.: N-Methyl— aspartate receptor subunit proteins and their phosphorylation status are altered selectively in Alzheimer's disease. J Neurol Sci. 2001; 182: 151-159. [DOI] [PubMed] [Google Scholar]
  25. Jain KK: Evaluation of memantine for neuroprotection in dementia. Expert Opin Investig Drugs. 2000; 9: 1397-1406. [DOI] [PubMed] [Google Scholar]
  26. Kornhuber J, Quack G: Cerebrospinal fluid and serum concentrations of the N-methyl-D-aspartate (NMDA) receptor antagonist memantine in man. Neurosci Lett. 1995; 195: 137-139. [DOI] [PubMed] [Google Scholar]
  27. Graham SM, Jonas JM, Lee GS, et al.: Memantine is safe for short- and long-term treatment of dementia. Neurobiol Aging.2004; 25: 195-195. [Google Scholar]
  28. Berger W, Deckert J, Hartmann J, et al.: Memantine inhibits [3H]MK-801 binding to human hippocampal NMDA receptors. NeuroReport. 1994; 5:1237-1240. [DOI] [PubMed] [Google Scholar]
  29. Frankiewicz T, Parsons CG: Memantine restores long term potentiation impaired by tonic N-methyl-D-aspartate (NMDA) receptor activation following reduction of Mg +2 in hippocampal slices. Neuropharmacology. 1999; 38: 1253-1259. [DOI] [PubMed] [Google Scholar]
  30. Pellegrini JW, Lipton SA: Delayed administration of memantine prevents N-methyl-D-aspartate receptor-mediated neurotoxicity. Ann Neurol.1993; 33:403-407. [DOI] [PubMed] [Google Scholar]
  31. Lahiri DK, Alley GM, Morgan C, et al.: Effects of memantine on levels of the amyloid beta peptide in cell cultures. Eur Neuropsychopharmacol. 2003; 13(Suppl 4):S391-S391. [Google Scholar]
  32. Lahiri DK, Bailey J, Alley GM, et al.: Effects of diverse cholinesterase inhibitors and memantine on the amyloid pathway and its implication in Alzheimer's disease. Neurobiol Aging.2004; 25: 63-63.14675732 [Google Scholar]
  33. Iqbal K, Liang Li, Sengupta A, et al.: Memantine restores the okadaic Acid induced changes in the activities of protein phosphatase-2A in rat hippocampal slices in culture. Eur Neuropsychopharmacol. 2003; 13(Suppl 4):S393-S394. [Google Scholar]
  34. Li L, Sengupta A, Haque N, et al.: Memantine inhibits and reserves the Alzheimer type abnormal hyperphosphorylation of tau and associated neurodegeneration. FEBS Lett. 2004; 556: 261-269. [DOI] [PubMed] [Google Scholar]
  35. Ahmed MM, Hoshino H, Chikuma T, et al.: Effect of memantine on the levels of glial cells, neuropeptide and peptide-degrading enzymes in rat brain regions of ibotenic acid-treated alzheimer's disease model. Neuroscience.2004; 126(3): 639-649. [DOI] [PubMed] [Google Scholar]
  36. Wenk GL, Zajaczkowski W, Danysz W: Neuroprotection of acetylcholinergic basal forebrain neurons by memantine and neurokinin B. Behav Brain Res. 1997; 83: 129-133. [DOI] [PubMed] [Google Scholar]
  37. Miguel-Hidalgo JJ, Alvarez XA, Cacabelos R, et al.: Neuroprotection by memantine against neurodegeneration induced by beta-amyloid (1-40). Brain Res. 2002; 958(1):210-221. [DOI] [PubMed] [Google Scholar]
  38. Miguel-Hidalgo JJ, Paul I, Wanzo V, et al.: Memantine prevents Aß 1-40-induced apoptotic cell death in the rat hippocampus. Neurobiol Aging. 2004; 25(Suppl 2): 415-415. [Google Scholar]
  39. Barnes CA, Danysz W, Parsons CG: Effects of the uncompetitive NMDA receptor antagonist memantine on hippocampal long term potentation, short-term exploratory modulation and spatial memory in awake, freely moving rats. Eur J Neurosci. 1996; 8: 565-571. [DOI] [PubMed] [Google Scholar]
  40. Tanila H, Minkeviciene R, Banerjee P: Behavioral effects of subchronic memantine treatment in APP/PS1 double mutant mice modeling Alzheimer's disease. Eur Neuropsychopharmacol. 2003; 13(Suppl 4): S392-S392. [Google Scholar]
  41. Minkeviviene R, Banerjee P, Tanila H. Memantine improves spatial learning in a transgenic mouse model of Alzheimer's disease. J Pharmacol Exp Ther. 2004; 311(2): 677-682. [DOI] [PubMed] [Google Scholar]
  42. Göertelmeyer R, Erbler H: Memantine in the treatment of mild to moderate dementia syndrome. Arzneimittelforschung. 1992; 42: 904-913. [PubMed] [Google Scholar]
  43. Pantev M, Ritter R, Göertelmeyer R: Clinical and behavioural evaluation in long term care patients with mild to moderate dementia under memantine treatment. Zeitschrift Gentopsychol Psychiatrie. 1993; 6: 103-117. [Google Scholar]
  44. Winblad B, Poritis N: Memantine in severe dementia: Results of the M-best study (benefit and efficacy in severely demented patients during treatment with memantine). Int J Geriatr Psychiatry. 1999; 14: 135-146. [DOI] [PubMed] [Google Scholar]
  45. Reisberg B, Doody R, Söffler A, et al.: Memantine in moderate to severe Alzheimer's disease. N Engl J Med. 2003; 348(14): 1333-1341. [DOI] [PubMed] [Google Scholar]
  46. Reisberg B, Möbius HJ, Schmidtt F, et al.: Long term efficacy and safety benefits from treatment with the NMDA antagonist memantine. Eur Neuropsychopharmacol. 2003; 13(Suppl 4): S388-S389. [Google Scholar]
  47. Rive B, Vercelleto M, Delamarre Damier F, et al.: Memantine enhances autonomy in moderate to severe Alzheimer's disease. Int J Geriatr Psychiatry. 2004; 19: 458-464. [DOI] [PubMed] [Google Scholar]
  48. Pomara N, Peskind ER, Potkin SG, et al.: Memantine monotherapy is effective and safe for the treatment of mild to moderate Alzheimer's disease: A randomised controlled trial. Neurobiol Aging. 2004; 25(Suppl 2): 19-19.14675725 [Google Scholar]
  49. Potkin SG, McDonald S, Gergel I, et al.: Memantine monotherapy increases brain metabolism (PET) and effectively treats mild to moderate Alzheimer's disease. Neurobiol Aging. 2004; 25(Suppl 2): 384-384. [Google Scholar]
  50. Tariot PN, Doody RS, Peskind ER, et al.: Memantine treatment for mild to severe Alzheimer's disease: Clinical trials summary. Neurobiol Aging. 2004; 25(Suppl 2): 99-99. [Google Scholar]
  51. Möbius HJ: Pharmacological rationale for memantine in chronic cerebral hypoperfusion, especially vascular dementia. Alzheimer Dis Assoc Disord. 1999; 13 (Suppl 3): S172-S178. [DOI] [PubMed] [Google Scholar]
  52. Wilcock G, Möbius HJ, Stöffler A: A double blind, placebo controlled multicenter study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol. 2002; 17(6): 297-305. [DOI] [PubMed] [Google Scholar]
  53. Orgogozo JM, Rigaud AS, Stoeffler A, et al.: Efficacy and safety of memantine in patients with mild to moderated vascular dementia. Stroke.2002; 33: 1834-1839. [DOI] [PubMed] [Google Scholar]
  54. Möbius HJ, Stöfler A: Memantine in vascular dementia. Int Psychogeriatr. 2003; 15(Suppl 1): 207-213. [DOI] [PubMed] [Google Scholar]
  55. Periclou A, Ventura D, Sherman T, et al.: Pharmakokinetic study of memantine and donepezil in healthy young subjects. Eur Neuropsychopharmacol. 2003; 13(Suppl 4): S398-S398. [Google Scholar]
  56. 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(3): 317-324. [DOI] [PubMed] [Google Scholar]
  57. Cummings J, Van Dyck C, Schmitt F, et al.: Functional and behavioral effects of memantine in AD. Neurobiol Aging. 2004; 25(Suppl 2): 186-186. [Google Scholar]

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

RESOURCES