Advertisement

CNS Drugs

, Volume 17, Issue 9, pp 641–652 | Cite as

The Glutamatergic System and Alzheimer’s Disease

Therapeutic Implications
  • D. Allan ButterfieldEmail author
  • Chava B. Pocernich
Review Article

Abstract

Alzheimer’s disease affects nearly 5 million Americans currently and, as a result of the baby boomer cohort, is predicted to affect 14 million Americans and 22 million persons totally worldwide in just a few decades. Alzheimer’s disease is present in nearly half of individuals aged 85 years.

The main symptom of Alzheimer’s disease is a gradual loss of cognitive function. Glutamatergic neurotransmission, an important process in learning and memory, is severely disrupted in patients with Alzheimer’s disease. Loss of glutamatergic function in Alzheimer’s disease may be related to the increase in oxidative stress associated with the amyloid β-peptide that is found in the brains of individuals who have the disease. Therefore, therapeutic strategies directed at the glutamatergic system may hold promise. Therapies addressing oxidative stress induced by hyperactivity of glutamate receptors include supplementation with estrogen and antioxidants such as tocopherol (vitamin E) and acetylcysteine (N-acetylcysteine). Therapy for hypoactivity of glutamate receptors is aimed at inducing the NMDA receptor with glycine and cycloserine (D-cycloserine). Recently, memantine, an NMDA receptor antagonist that addresses the hyperactivity of these receptors, has been approved in some countries for use in Alzheimer’s disease.

Keywords

NMDA Receptor Glutamine Synthetase Memantine Glutamate Transporter Glutamate Uptake 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

This work was supported in part by grants from the National Institutes of Health (AG-10836; AG-05119). The authors have no conflicts of interest with regard to the contents of this manuscript.

References

  1. 1.
    Katzman R, Saitoh T. Advances in Alzheimer’s disease. FASEB J 1991; 5: 278–86PubMedGoogle Scholar
  2. 2.
    Katzman R. Epidemiology of Alzheimer’s disease. Neurobiol Aging 2000; 21 Suppl.: S1CrossRefGoogle Scholar
  3. 3.
    Glenner GG, Wong CW. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984; 120: 885–90PubMedCrossRefGoogle Scholar
  4. 4.
    Masters CL, Simms G, Weinman NA, et al. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A 1985; 82: 4245–9PubMedCrossRefGoogle Scholar
  5. 5.
    Yankner BA, Dawes LR, Fisher S, et al. Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer’s disease. Science 1989; 245: 417–20PubMedCrossRefGoogle Scholar
  6. 6.
    Frautschy SA, Baird A, Cole GM. Effects of injected Alzheimer beta-amyloid cores in rat brain. Proc Natl Acad Sci U S A 1991; 88: 8362–6PubMedCrossRefGoogle Scholar
  7. 7.
    Kowall NW, Beal MF, Busciglio J, et al. An in vivo model for the neurodegenerative effects of beta amyloid and protection by substance P. Proc Natl Acad Sci U S A 1991; 88: 7247–51PubMedCrossRefGoogle Scholar
  8. 8.
    Pike CJ, Walencewicz AJ, Glabe CG, et al. In vitro aging of beta-amyloid protein causes peptide aggregation and neurotoxicity. Brain Res 1991; 563: 311–4PubMedCrossRefGoogle Scholar
  9. 9.
    Howlett DR, Jennings KH, Lee DC, et al. Aggregation state and neurotoxic properties of Alzheimer beta-amyloid peptide. Neurodegeneration 1995; 4: 23–32PubMedCrossRefGoogle Scholar
  10. 10.
    Harris ME, Hensley K, Butterfield DA, et al. Direct evidence of oxidative injury produced by the Alzheimer’s beta-amyloid peptide (1-40) in cultured hippocampal neurons. Exp Neurol 1995; 131: 193–202PubMedCrossRefGoogle Scholar
  11. 11.
    Aksenov MY, Aksenova MV, Butterfield DA, et al. Glutamine synthetase-induced enhancement of beta-amyloid peptide A beta (1-40) neurotoxicity accompanied by abrogation of fibril formation and A beta fragmentation. J Neurochem 1996; 66: 2050–6PubMedCrossRefGoogle Scholar
  12. 12.
    Aksenov MY, Aksenova MV, Markesbery WR, et al. Amyloid beta-peptide (1-40)-mediated oxidative stress in cultured hippocampal neurons: protein carbonyl formation, CK BB expression, and the level of Cu, Zn, and Mn SOD mRNA. J Mol Neurosci 1998; 10: 181–92PubMedCrossRefGoogle Scholar
  13. 13.
    Yatin SM, Aksenov M, Butterfield DA. The antioxidant vitamin E modulates amyloid beta-peptide-induced creatine kinase activity inhibition and increased protein oxidation: implications for the free radical hypothesis of Alzheimer’s disease. Neurochem Res 1999; 24: 427–35PubMedCrossRefGoogle Scholar
  14. 14.
    Yatin SM, Varadarajan S, Link C, et al. In vitro and in vivo oxidative stress associated with Alzheimer’s amyloid beta-peptide (1-42). Neurobiol Aging 1999; 20: 325–30PubMedCrossRefGoogle Scholar
  15. 15.
    Yatin SM, Aksenova M, Aksenov M, et al. Effect of transglutaminase on Aβ(1-40) fibril formation and neurotoxicity. Alzheimer Rep 1999; 2: 165–70Google Scholar
  16. 16.
    Varadarajan S, Yatin S, Kanski J, et al. Methionine residue 35 is important in amyloid beta-peptide-associated free radical oxidative stress. Brain Res Bull 1999; 50: 133–41PubMedCrossRefGoogle Scholar
  17. 17.
    Varadarajan S, Yatin S, Aksenova M, et al. Review: Alzheimer’s amyloid-peptide-associated free radical oxidative stress and neurotoxicity. J Struct Biol 2000; 130: 184–208PubMedCrossRefGoogle Scholar
  18. 18.
    Aksenov MY, Aksenova MV, Harris ME, et al. Enhancement of beta-amyloid peptide A beta(1-40)-mediated neurotoxicity by glutamine synthetase. J Neurochem 1995; 65: 1899–902PubMedCrossRefGoogle Scholar
  19. 19.
    Yatin SM, Yatin M, Aulick T, et al. Alzheimer’s amyloid betapeptide associated free radicals increase rat embryonic neuronal polyamine uptake and ornithine decarboxylase activity: protective effect of vitamin E. Neurosci Lett 1999; 263: 17–20PubMedCrossRefGoogle Scholar
  20. 20.
    Selkoe DJ. Amyloid beta-protein and the genetics of Alzheimer’s disease. J Biol Chem 1996; 271: 18295–8PubMedGoogle Scholar
  21. 21.
    Scheuner D, Eckman C, Jensen M, et al. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 1996; 8: 864–70CrossRefGoogle Scholar
  22. 22.
    Teller JK, Russo C, DeBusk L, et al. Presence of soluble amyloid beta-peptide precedes amyloid plaque formation in Down’s syndrome. Nat Med 1996; 2: 93–5PubMedCrossRefGoogle Scholar
  23. 23.
    Games D, Adams D, Alessandrini R, et al. Alzheimer-type neuropathology in transgenic mice overexpressing V717F beta-amyloid precursor protein. Nature 1995; 373: 523–7PubMedCrossRefGoogle Scholar
  24. 24.
    Hsiao K, Chapman P, Nilsen S, et al. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science 1996; 274: 99–102PubMedCrossRefGoogle Scholar
  25. 25.
    Hsiao K. Transgenic mice expressing Alzheimer amyloid precursor proteins. Exp Gerontol 1998; 33: 883–9PubMedCrossRefGoogle Scholar
  26. 26.
    Masliah E, Sisk A, Mallory M, et al. Comparison of neurodegenerative pathology in transgenic mice overexpressing V717F beta-amyloid precursor protein and Alzheimer’s disease. J Neurosci 1996; 16: 5795–811PubMedGoogle Scholar
  27. 27.
    Irizarry MC, McNamara M, Fedorchak K, et al. APPSw transgenic mice develop age-related A beta deposits and neuropil abnormalities, but no neuronal loss in CA 1. J Neuropathol Exp Neurol 1997; 56: 965–73PubMedCrossRefGoogle Scholar
  28. 28.
    Sturchler-Pierrat C, Abramowski D, Duke M, et al. Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A 1997; 94: 13287–92PubMedCrossRefGoogle Scholar
  29. 29.
    Calhoun ME, Wiederhold KH, Abramowski D, et al. Neuron loss in APP transgenic mice. Nature 1998; 395: 755–6PubMedCrossRefGoogle Scholar
  30. 30.
    Frautschy SA, Yang F, Irrizarry M, et al. Microglial response to amyloid plaques in APPsw transgenic mice. Am J Pathol 1998; 152: 307–17PubMedGoogle Scholar
  31. 31.
    Pappolla MA, Chyan YJ, Omar RA, et al. Evidence of oxidative stress and in vivo neurotoxicity of beta-amyloid in a transgenic mouse model of Alzheimer’s disease: a chronic oxidative paradigm for testing antioxidant therapies in vivo. Am J Pathol 1998; 152: 871–7PubMedGoogle Scholar
  32. 32.
    Smith MA, Hirai K, Hsiao K, et al. Amyloid-beta deposition in Alzheimer transgenic mice is associated with oxidative stress. J Neurochem 1998; 70: 2212–5PubMedCrossRefGoogle Scholar
  33. 33.
    Lambert MP, Barlow AK, Chromy BA, et al. Diffusible, nonfibrillar ligands derived from Abetal-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A 1998; 95: 6448–53PubMedCrossRefGoogle Scholar
  34. 34.
    Walsh DM, Klyubin I, Fadeeva JV, et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 2002; 416: 535–9PubMedCrossRefGoogle Scholar
  35. 35.
    Drake J, Link CD, Butterfield DA. Oxidative stress precedes fibrillar deposition of Alzheimer’s disease amyloid β-peptide (1-42) in a transgenic Caenorhabditis elegans model. Neurobiol Aging 2003; 24: 415–20PubMedCrossRefGoogle Scholar
  36. 36.
    Butterfield DA, Drake J, Pocernich C, et al. Evidence of oxidative damage in Alzheimer’s disease brain: central role for amyloid beta-peptide. Trends Mol Med 2001; 7: 548–54PubMedCrossRefGoogle Scholar
  37. 37.
    Varadarajan S, Kanski J, Aksenova M, et al. Different mechanisms of oxidative stress and neurotoxicity for Alzheimer’s A beta(1-42) and A beta(25-35). J Am Chem Soc 2001; 123: 5625–31PubMedCrossRefGoogle Scholar
  38. 38.
    Butterfield DA, Lauderback CM. Lipid peroxidation and protein oxidation in Alzheimer’s disease brain: potential causes and consequences involving amyloid-peptide-associated free radical oxidative stress. Free Radie Biol Med 2002; 32: 1050–60CrossRefGoogle Scholar
  39. 39.
    Butterfield DA, Castegna A, Lauderback CM, et al. Evidence that amyloid beta-peptide-induced lipid peroxidation and its sequelae in Alzheimer’s disease brain contributes to neuronal death. Neurobiol Aging 2002; 23: 655–64PubMedCrossRefGoogle Scholar
  40. 40.
    Lauderback CM, Hackett JM, Huang FF, et al. The glial glutamate transporter, GLT-1, is oxidatively modified by 4-hydroxy-2-nonenal in the Alzheimer’s disease brain: the role of Aβ1-42. J Neurochem 2001; 78: 413–6PubMedCrossRefGoogle Scholar
  41. 41.
    Aksenov MY, Aksenova MV, Carney JM, et al. Oxidative modification of glutamine synthetase by amyloid beta peptide. Free Radic Res 1997; 27: 267–81PubMedCrossRefGoogle Scholar
  42. 42.
    Butterfield DA, Hensley K, Cole P, et al. Oxidatively induced structural alteration of glutamine synthetase assessed by analysis of spin label incorporation kinetics: relevance to Alzheimer’s disease. J Neurochem 1997; 68: 2451–7PubMedCrossRefGoogle Scholar
  43. 43.
    Mattson MP, Cheng B, Culwell AR, et al. Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein. Neuron 1993; 10: 243–54PubMedCrossRefGoogle Scholar
  44. 44.
    Culcasi M, Lafon-Cazal M, Pietri S, et al. Glutamate receptors induce a burst of superoxide via activation of nitric oxide synthase in arginine-depleted neurons. J Biol Chem 1994; 269: 12589–93PubMedGoogle Scholar
  45. 45.
    Kennedy MB. Signal-processing machines at the postsynaptic density. Science 2000; 290: 750–4PubMedCrossRefGoogle Scholar
  46. 46.
    Sheng M, Kim MJ. Postsynaptic signaling and plasticity mechanisms. Science 2002; 298: 776–80PubMedCrossRefGoogle Scholar
  47. 47.
    Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science 2002; 298: 789–91PubMedCrossRefGoogle Scholar
  48. 48.
    Terry RD, Masliah E, Salmon DP, et al. Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 1991; 30: 572–80PubMedCrossRefGoogle Scholar
  49. 49.
    Davies CA, Mann DM, Sumpter PQ, et al. A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer’s disease. J Neurol Sci 1987; 78: 151–64PubMedCrossRefGoogle Scholar
  50. 50.
    Collingridge GL, Singer W. Excitatory amino acid receptors and synaptic plasticity. Trends Pharmacol Sci 1990; 11: 290–6PubMedCrossRefGoogle Scholar
  51. 51.
    Myhrer T. Adverse psychological impact, glutamatergic dysfunction, and risk factors for Alzheimer’s disease. Neurosci Biobehav Rev 1998; 23: 131–9PubMedCrossRefGoogle Scholar
  52. 52.
    Furuta A, Rothstein JD, Martin JL. Glutamate transporter protein subtypes are expressed differentially during rat central nervous system development. J Neurosci 1997; 17: 8363–75PubMedGoogle Scholar
  53. 53.
    Sims KD, Robinson MB. Expression patterns and regulation of glutamate transporters in the developing and adult nervous system. Crit Rev Neurobiol 1999; 13: 169–97PubMedGoogle Scholar
  54. 54.
    Lehre KP, Levy LM, Otterson OP, et al. Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations. J Neurosci 1995; 15: 1835–53PubMedGoogle Scholar
  55. 55.
    Greenamyre JT, Young AB. Excitatory amino acids and Alzheimer’s disease. Neurobiol Aging 1989; 10: 593–602PubMedCrossRefGoogle Scholar
  56. 56.
    Gordon-Krajcer W, Salinska E, Lazarewicz JW. N-methyl-d-aspartate receptor-mediated processing of beta-amyloid precursor protein in rat hippocampal slices: in vitro-superfusion study. Folia Neuropathol 2002; 40: 13–7PubMedGoogle Scholar
  57. 57.
    Kamenetz F, Tomita T, Hsieh H, et al. APP processing and synaptic function. Neuron 2003; 37: 925–37PubMedCrossRefGoogle Scholar
  58. 58.
    Raymond CR, Ireland DR, Abraham WC. NMDA receptor regulation by amyloid-beta does not account for its inhibition of LTP in rat hippocampus. Brain Res 2003; 968: 263–72PubMedCrossRefGoogle Scholar
  59. 59.
    Greenamyre JT. The role of glutamate in neurotransmission and neurologic disease. Arch Neurol 1986; 43: 1058–63PubMedCrossRefGoogle Scholar
  60. 60.
    Maragos WF, Greenamyre JT, Penney JB, et al. Glutamate dysfunction in Alzheimer’s disease: an hypothesis. TINS 1987; 10: 65–8Google Scholar
  61. 61.
    Palmer AM, Gershon S. Is the neuronal basis of Alzheimer’s disease cholinergic or glutamatergic? FASEB J 1990; 4: 2745–52PubMedGoogle Scholar
  62. 62.
    Antuono PG, Jones JL, Wang Y, et al. Decreased glutamate + glutamine in Alzheimer’s disease detected in vivo with 1H-MRS at 0.5T. Neurology 2001; 56: 737–42PubMedCrossRefGoogle Scholar
  63. 63.
    Moats RA, Ernst T, Shonk TK, et al. Abnormal cerebral metabolite concentrations in patients with probable Alzheimer disease. Magn Reson Med 1994; 32: 110–5PubMedCrossRefGoogle Scholar
  64. 64.
    Ernst T, Chang L, Melchor R, et al. Frontotemporal dementia and early Alzheimer disease: differentiation with frontal lobe H-1 MR spectroscopy. Radiology 1997; 203: 829–36PubMedGoogle Scholar
  65. 65.
    Castegna A, Aksenov M, Aksenova M, et al. Proteomic identification of oxidatively modified proteins in Alzheimer’s disease brain. Part I: creatine kinase BB, glutamine synthase, and ubiquitin carboxy-terminal hydrolase L-1. Free Radic Biol Med 2002; 33: 562–71PubMedCrossRefGoogle Scholar
  66. 66.
    Hensley K, Hall N, Subramaniam R, et al. Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation. J Neurochem 1995; 65: 2146–56PubMedCrossRefGoogle Scholar
  67. 67.
    Butterfield DA. Beta-amyloid-associated free radical oxidative stress and neurotoxicity: implications for Alzheimer’s disease. Chem Res Toxicol 1997; 10: 495–506PubMedCrossRefGoogle Scholar
  68. 68.
    Masliah E, Alford M, DeTeresa R, et al. Deficient glutamate transport is associated with neurodegeneration in Alzheimer’s disease. Ann Neurol 1996; 40: 759–66PubMedCrossRefGoogle Scholar
  69. 69.
    Scott HL, Tannenberg A, Dodd PR. Variant forms of neuronal glutamate transporter sites in Alzheimer’s disease cerebral cortex. J Neurochem 1995; 64: 2193–202PubMedCrossRefGoogle Scholar
  70. 70.
    Butterfield DA, Hensley K, Harris M, et al. beta-Amyloid peptide free radical fragments initiate synaptosomal lipoperoxidation in a sequence-specific fashion: implications to Alzheimer’s disease. Biochem Biophys Res Commun 1994; 200(2): 710–5PubMedCrossRefGoogle Scholar
  71. 71.
    Thal DR. Excitatory amino acid transporter EAAT-2 in tangle-bearing neurons in Alzheimer’s disease. Brain Pathol 2002; 12: 405–11CrossRefGoogle Scholar
  72. 72.
    Boissiere F, Faucheux B, Duyckaerts C, et al. Striatal expression of glutamic acid decarboxylase gene in Alzheimer’s disease. Neurochem 1998; 71: 767–74CrossRefGoogle Scholar
  73. 73.
    Hertz L, Drejer J, Schousboe A. Energy metabolism in glutamatergic neurons, GABAergic neurons and astrocytes in primary cultures. Neurochem Res 1988; 13: 605–10PubMedCrossRefGoogle Scholar
  74. 74.
    Marczynski TJ. GABAergic deafferentation hypothesis of brain aging and Alzheimer’s disease revisited. Brain Res Bull 1998; 45: 341–79PubMedCrossRefGoogle Scholar
  75. 75.
    Haug LS, Ostvold AC, Cowburn RF, et al. Decreased inositol (1,4,5)-trisphosphate receptor levels in Alzheimer’s disease cerebral cortex: selectivity of changes and possible correlation to pathological severity. Neurodegeneration 1996; 5: 169–76PubMedCrossRefGoogle Scholar
  76. 76.
    Kowall NW, Beal MF. Glutamate-, glutaminase-, and taurine-immunoreactive neurons develop neurofibrillary tangles in Alzheimer’s disease. Ann Neurol 1991; 29: 162–7PubMedCrossRefGoogle Scholar
  77. 77.
    Olney JW, Wozniak DF, Farber NB. Excitotoxic neurodegeneration in Alzheimer’s disease: new hypothesis and new therapeutic strategies. Arch Neurol 1997; 54: 1234–40PubMedCrossRefGoogle Scholar
  78. 78.
    Drake J, Kanski J, Varadarajan S, et al. Elevation of brain glutathione by glutamylcysteine ethyl ester protects against peroxynitrite-induced oxidative stress. J Neurosci Res 2002; 68: 776–84PubMedCrossRefGoogle Scholar
  79. 79.
    Butterfield DA, Pocernich CB, Drake J. Elevated glutathione as a therapeutic strategy in Alzheimer’s disease. Drug Dev Res 2002; 56: 428–37CrossRefGoogle Scholar
  80. 80.
    Pocernich CB, Cardin AL, Racine CL, et al. Glutathione elevation and its protective role in acrolein-induced protein damage in synaptosomal membranes: relevance to brain lipid peroxidation in neurodegenerative disease. Neurochem Int 2001; 39(2): 141–9PubMedCrossRefGoogle Scholar
  81. 81.
    Butterfield DA, Castenga A, Pocernich CB, et al. Nutritional approaches to combat oxidative stress in Alzheimer’s disease brain. J Nutr Biochem 2002; 13: 444–8PubMedCrossRefGoogle Scholar
  82. 82.
    Butterfield DA, Castegna A, Drake J, et al. Vitamin E and neurodegenerative disorders associated with oxidative stress. Nutr Neurosci 2002; 5: 229–39PubMedCrossRefGoogle Scholar
  83. 83.
    Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer’s disease: the Alzheimer’s Disease Cooperative Study. N Engl J Med 1997; 336: 1216–22PubMedCrossRefGoogle Scholar
  84. 84.
    Onofrj M, Thomas A, Luciano AL, et al. Donepezil versus vitamin E in Alzheimer’s disease. Part 2: mild versus moderate-severe Alzheimer’s disease. Clin Neuropharmacol 2002; 25: 207–15Google Scholar
  85. 85.
    Adair JC, Knoefel JE, Morgan N. Controlled trial of N-acetylcysteine for patients with probable Alzheimer’s disease. Neurology 2001; 57: 1515–7PubMedCrossRefGoogle Scholar
  86. 86.
    Gandolfi O, Bonfante V, Voltattorni M, et al. Anticonvulsant preclinical profile of CHF 3381: dopaminergic and glutamatergic mechanisms. Pharmacol Biochem Behav 2001; 70: 157–66PubMedCrossRefGoogle Scholar
  87. 87.
    Coughenour LL, Barr BM. Use of trifluoroperazine isolates a [(3)H]ifenprodil binding site in rat brain membranes with the pharmacology of the voltage-independent ifenprodil site on N-methyl-D-aspartate receptors containing NR2B subunits. J Pharmacol Exp Ther 2001; 296: 150–9PubMedGoogle Scholar
  88. 88.
    Rubin MA, Stiegemeier JA, Volkweis MA, et al. Intra-amygdala spermidine administration improves inhibitory avoidance performance in rats. Eur J Pharmacol 2001; 423: 35–9PubMedCrossRefGoogle Scholar
  89. 89.
    Zhang YH, Zhao XY, Chen XQ, et al. Spermidine antagonizes the inhibitory effect of huperzine A on [3H]dizocilpine (MK-801) binding in synaptic membrane of rat cerebral cortex. Neurosci Lett 2002; 319: 107–10PubMedCrossRefGoogle Scholar
  90. 90.
    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: 735–67PubMedCrossRefGoogle Scholar
  91. 91.
    Leppik IE, Marienau K, Graves NM, et al. MK-801 for epilepsy: a pilot study [abstract]. Neurology 1988; 38: 405CrossRefGoogle Scholar
  92. 92.
    Sveinbjornsdottir S, Sander JWAS, Upton D, et al. The excitatory amino acid antagonist D-CPP-ene (SDZ EAA-494) in patients with epilepsy. Epilepsy Res 1993; 16: 165–74PubMedCrossRefGoogle Scholar
  93. 93.
    Yenari MA, Bell TE, Kotake AN, et al. Dose escalation safety and tolerance study of the competitive NMDA antagonist selfotel (CGS 19755) in neurosurgery patients. Clin Neuropharmacol 1998; 21: 28–34PubMedGoogle Scholar
  94. 94.
    Barnes CA, Danysz W, Parsons CG. Effects of the uncompetitive NMDA receptor antagonist memantine on hippocampal long-term potentiation, short-term exploratory modulation and spatial memory in awake, freely moving rats. Eur J Neurosci 1996; 8: 565–71PubMedCrossRefGoogle Scholar
  95. 95.
    Zajaczkowski W, Quack G, Danysz W. Infusion of (+)-MK-801 and memantine: contrasting effects on radial maze learning in rats with entorhinal cortex lesion. Eur J Pharmacol 1996; 296: 239–46PubMedCrossRefGoogle Scholar
  96. 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: 210–21PubMedCrossRefGoogle Scholar
  97. 97.
    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: 135–46PubMedCrossRefGoogle Scholar
  98. 98.
    Jarvis B, Figgitt D. Memantine. Drugs Aging 2003; 20: 465–76PubMedCrossRefGoogle Scholar
  99. 99.
    Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003; 348: 1333–41PubMedCrossRefGoogle Scholar
  100. 100.
    Wimo A, Winblad B, Stoffler A, et al. Resource utilisation and cost analysis of memantine in patients with moderate to severe Alzheimer’s disease. Pharmacoeconomics 2003; 21: 327–40PubMedCrossRefGoogle Scholar
  101. 101.
    Ferris SH, Schmidt F, Doody R, et al. Long-term treatment with the NMDA antagonist, memantine: results of a 24-week, open-label extension study in advanced Alzheimer’s disease [poster]. Annual Meeting of the American College of Neuropsychopharmacology; 2001 Dec 9–13; Waikoloa Village (HI)Google Scholar
  102. 102.
    Kilpatrick GJ, Tilbrook GS. Memantine: Merz. Curr Opin Investig Drugs 2002; 3: 798–806PubMedGoogle Scholar
  103. 103.
    Jain KK. Evaluation of memantine for neuroprotection in dementia. Expert Opin Investig Drugs 2000; 9: 1397–406PubMedCrossRefGoogle Scholar
  104. 104.
    Wenk GL, Quack G, Moebius HJ, et al. No interaction of memantine with acetylcholinesterase inhibitors approved for clinical use. Life Sci 2000; 66: 1079–83PubMedCrossRefGoogle Scholar
  105. 105.
    Farlow MR, Tariot PN, Grossberg GT, et al. Memantine/donepezil dual therapy is superior to placebo/donepezil therapy for treatment of moderate to severe Alzheimer’s disease [abstract no. 1035]. Neurology 2003; 60Suppl. 1: A412Google Scholar
  106. 106.
    Danysz W, Parsons CG, Jirgensons A, et al. Amino-alkylcyclohexanes as a novel class of uncompetitive NMDA receptor antagonists. Curr Pharm Des 2002; 8: 835–43PubMedCrossRefGoogle Scholar
  107. 107.
    Liang Z, Valla J, Sefidvash-Hockley S, et al. Effects of estrogen treatment on glutamate uptake in cultured human astrocytes derived from cortex of Alzheimer’s disease patients. J Neurochem 2002; 80: 807–14PubMedCrossRefGoogle Scholar
  108. 108.
    Xu H, Gouras GK, Greenfield JP, et al. Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nat Med 1998; 4: 447–51PubMedCrossRefGoogle Scholar
  109. 109.
    Li R, Shen Y, Yang L-B, et al. Estrogen enhances uptake of amyloid protein by microglia derived from the human cortex. J Neurochem 2000; 75: 14447–54Google Scholar
  110. 110.
    Zheng H, Xu H, Uljon SN, et al. Modulation of A(beta) peptides by estrogen in mouse models. J Neurochem 2002; 80: 191–6PubMedCrossRefGoogle Scholar
  111. 111.
    Keller JN, Germeyer A, Begley JG, et al. 17-Estradiol attenuates oxidative impairment of synaptic Na/K-ATPase activity, glucose transport, and glutamate transport induced by amyloid b-peptide and ion. J Neurosci Res 1997; 50: 522–30PubMedCrossRefGoogle Scholar
  112. 112.
    Trotti D, Danbolt NC, Volterra A. Glutamate transporters are oxidant-vulnerable: a molecular link between oxidative and excitotoxic neurodegeneration? Trends Pharmacol Sci 1998; 19: 328–34PubMedCrossRefGoogle Scholar
  113. 113.
    Singer C, Rogers KL, Strickland TM, et al. Estrogen protects primary cortical neurons from glutamate toxicity. Neurosci Lett 1996; 212: 13–6PubMedCrossRefGoogle Scholar
  114. 114.
    Green PS, Perez EJ, Calloway T, et al. Estradiol attenuation of beta-amyloid-induced toxicity: a comparison of MTT and calcein AM assays. J Neurocytol 2000; 29: 419–23PubMedCrossRefGoogle Scholar
  115. 115.
    Asthana S, Craft S, Baker LD, et al. Cognitive and neuroendocrine response to transdermal estrogen in postmenopausal women with Alzheimer’s disease: results of a placebo-controlled, double-blind, pilot study. Psychoneuroendocrinology 1999; 24: 657–77PubMedCrossRefGoogle Scholar
  116. 116.
    Asthana S, Baker LD, Craft S, et al. High-dose estradiol improves cognition for women with AD: results of a randomized study. Neurology 2001; 57: 605–12PubMedCrossRefGoogle Scholar
  117. 117.
    Yoon BK, Kim DK, Kang Y, et al. Hormone replacement therapy in postmenopausal women with Alzheimer’s disease: a randomized, prospective study. Fertil Steril 2003; 79: 274–80PubMedCrossRefGoogle Scholar
  118. 118.
    Thal LJ, Thomas RG, Mulnard R, et al. Estrogen levels do not correlate with improvement in cognition. Arch Neurol 2003; 60: 209–12PubMedCrossRefGoogle Scholar
  119. 119.
    Mulnard RA, Cotman CW, Kawas C, et al. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial: Alzheimer’s Disease Cooperative Study. JAMA 2000; 283: 1007–15PubMedCrossRefGoogle Scholar
  120. 120.
    Henderson VW, Paganini-Hill A, Miller BL, et al. Estrogen for Alzheimer’s disease in women: randomized, double-blind, placebo-controlled trial. Neurology 2000; 54: 295–301PubMedCrossRefGoogle Scholar
  121. 121.
    Rigaud AS, Andre G, Vellas B, et al. No additional benefit of HRT on response to rivastigmine in menopausal women with AD. Neurology 2003; 60: 148–9PubMedCrossRefGoogle Scholar
  122. 122.
    Owens CT. Estrogen replacement therapy for Alzheimer disease in postmenopausal women. Ann Pharmacother 2002; 36: 1273–6PubMedCrossRefGoogle Scholar
  123. 123.
    Shumaker SA, Reboussin BA, Espeland MA, et al. The Women’s Health Initiative Memory Study (WHIMS): a trial of the effect of estrogen therapy in preventing and slowing the progression of dementia. Control Clin Trials 1998; 19: 604–21PubMedCrossRefGoogle Scholar
  124. 124.
    MacLennan AH, Paine BJ, Marley JE. WISDOM: will Australian women participate? Aust Fam Physician 2000; 29: 797–801PubMedGoogle Scholar
  125. 125.
    Myhrer T. Animal models of Alzheimer’s disease: glutamatergic denervation as an alternative approach to cholinergic denervation. Neurosci Biobehav Rev 1993; 17: 192–202CrossRefGoogle Scholar
  126. 126.
    Steele JE, Palmer AM, Stratmann GC, et al. The N-methyl-D-aspartate receptor complex in Alzheimer’s disease: reduced regulation by glycine but not zinc. Brain Res 1989; 500: 369–73PubMedCrossRefGoogle Scholar
  127. 127.
    Herting RL. Milacemide and other drugs active at glutamate NMDA receptors as potential treatment for dementia. Ann N Y Acad Sci 1991; 640: 237–40PubMedGoogle Scholar
  128. 128.
    Schwartz BL, Hashtroudi RL, Herting H, et al. Glycine prodrug facilitates memory retrieval in humans. Neurology 1991; 41: 1341–3PubMedCrossRefGoogle Scholar
  129. 129.
    Flood JF, Morley JE, Lanthorn TH. Effect on memory processing by D-cycloserine, an agonist of the NMDA/glycine receptor. Eur J Pharmacol 1992; 221: 249–54PubMedCrossRefGoogle Scholar
  130. 130.
    Monahan JB, Handelmann GE, Hood WF, et al. D-cycloserine, a positive modulator of the N-methyl-D-aspartate receptor enhances performance of learning tasks in rats. Pharmacol Biochem Behav 1989; 34: 649–53PubMedCrossRefGoogle Scholar
  131. 131.
    Chessell IP, Proctor AW, Francis PT, et al. D-cycloserine, a putative cognitive enhancer, facilitates activation of N-methyl-D-aspartate receptor-ionophore complex in Alzheimer brain. Brain Res 1991; 565: 345–8PubMedCrossRefGoogle Scholar
  132. 132.
    Schwartz BL, Hashtroudi S, Herting RL, et al. D-cycloserine enhances implicit memory in Alzheimer patients. Neurology 1996; 46: 420PubMedCrossRefGoogle Scholar
  133. 133.
    Shimada A, Spangler EL, London ED, et al. Spermidine potentiates dizocilpine-induced impairment of learning performance by rats in a 14-unit T-maze. Eur J Pharmacol 1994; 263: 293–30PubMedCrossRefGoogle Scholar
  134. 134.
    Zhang S, Kashii S, Yasuyoshi H, et al. Protective effects of ifenprodil against glutamate-induced neurotoxicity in cultured retinal neurons. Graefes Arch Clin Exp Ophthalmol 2000; 238: 846–52PubMedCrossRefGoogle Scholar
  135. 135.
    Gmiro VE, Serdiuk SE. Bis-ammonium adamantane derivatives: novel modulators of polyamine binding sites. Eksp Klin Farmakol 2000; 63: 16–20Google Scholar
  136. 136.
    Yatin SM, Yatin M, Varadarajan S, et al. Role of spermine in amyloid beta-peptide-associated free radical-induced neurotoxicity. J Neurosci Res 2001; 63: 395–401PubMedCrossRefGoogle Scholar
  137. 137.
    Guldbrandt M, Johansen TN, Frydenvang K, et al. Glutamate receptor ligands: synthesis, stereochemistry, and enantiopharmacology of methylated 2-aminoadipic acid analogs. Chirality 2002; 14: 351–63PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  1. 1.Department of Chemistry, Center of Membrane Sciences and Sanders-Brown Center on AgingUniversity of KentuckyLexingtonUSA

Personalised recommendations