Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond

Key Points

  • Excessive NMDA-type glutamate receptor activity is thought to contribute to a wide range of neurologic disorders, but multiple antagonists of this target have all failed in human trials because of poor clinical tolerability.

  • It became clear that therapeutic strategies had to change if the NMDA receptor was to be approached clinically. This review highlights the recent realization that uncompetitive, low-affinity (weakly binding) yet specific antagonists with fast off rates can block excessive NMDA receptor activity while sparing normal activity. This concept has led to successful clinical trials with the drug memantine. The action of an uncompetitive antagonist is contingent upon prior activation of the receptor by the agonist, and, as a result, uncompetitive antagonists, such as memantine, preferentially block increasing (pathological) levels of activity, while relatively sparing normal activity.

  • Studies in both human and rodent models have shown that Vascular dementia, Alzheimer's disease, stroke, HIV-associated dementia, glaucoma, multiple sclerosis, epilepsy, Parkinson's disease, Huntington's disease, motor neuron disease, neuropathic pain, and other neurologic disorders may all manifest a component of NMDA receptor-mediated cell damage.

  • Clinical trials have shown that the NMDA receptor antagonist, memantine, an open-channel blocker, can be helpful for moderate-to-severe Alzheimer's disease. Other clinical trials have suggested that the drug is also effective in Vascular dementia, and a series of additional trials are in progress for other indications.

  • Second-generation drugs, represented by the Nitro Memantines, may prove even more effective than memantine by manifesting a second site of action at redox-active thiols on critical regulatory cysteine residues, where nitric oxide (NO) can react via a mechanism designated S-nitrosylation.

  • Perhaps the most promising aspect of such NMDA receptor drugs is that the simple concept of uncompetitive inhibition could be extended to other neuroprotective targets and, more generally, even to other pharmaceutical targets. This approach can enhance clinical tolerability of drugs by avoiding effects on normal activity of the target, and thus may well represent the future of drug development

Abstract

Neuroprotective drugs tested in clinical trials, particularly those that block N-methyl-D-aspartate-sensitive glutamate receptors (NMDARs), have failed miserably in large part because of intolerable side effects. However, one such drug, memantine, was recently approved by the European Union and the US FDA for the treatment of dementia following our group's discovery of its clinically tolerated mechanism of action. Here, we review the molecular basis for memantine efficacy in neurological diseases that are mediated, at least in part, by overactivation of NMDARs, producing excessive Ca2+ influx through the receptor's associated ion channel and consequent free-radical formation.

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Figure 1: Schema of the apoptotic-like cell injury and death pathways triggered by excessive NMDAR activity.
Figure 2: NMDAR model illustrating important binding and modulatory sites.
Figure 3: Chemical structure of memantine.
Figure 4: Blockade of NMDA current by memantine.
Figure 5: Uncompetitive inhibition by memantine.
Figure 6: Effect of memantine on single-channel recordings.
Figure 7: Relative lack of effect of memantine on NMDA receptor component of excitatory postsynaptic currents (EPSCs).

References

  1. 1

    Lipton, S. A. & Rosenberg, P. A. Mechanisms of disease: Excitatory amino acids as a final common pathway for neurologic disorders. N. Engl. J. Med. 330, 613–622 (1994).

  2. 2

    Lipton, S. A. & Nicotera, P. Calcium, free radicals and excitotoxins in neuronal apoptosis. Cell Calcium 23, 165–171 (1998).

  3. 3

    Choi, D. W. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1, 623–634 (1988).

  4. 4

    Meldrum, B. & Garthwaite, J. Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol. Sci. 11, 379–387 (1990).

  5. 5

    Rothman, S. M. & Olney, J. W. Excitotoxicity and the NMDA receptor. Trends Neurosci. 10, 299–302 (1987).

  6. 6

    Zeevalk, G. D. & Nicklas, W. J. Evidence that the loss of the voltage-dependent Mg2+ block of the N-methyl-D-aspartate receptor underlies receptor activation during inhibition of neuronal metabolism. J. Neurochem. 59, 1211–1220 (1992).

  7. 7

    Hardingham, G. E., Fukunaga, Y. & Bading, H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nature Neurosci. 5, 405–414 (2002). This was the first paper to report that NMDAR-mediated synaptic activity was neuroprotective whereas extrasynatpic (presumably excessive) activity contributed to neuronal cell injury and death.

  8. 8

    Kemp, J. A. & McKernan, R. M. NMDA receptor pathways as drug targets. Nat. Neurosci. 5 (Suppl.), 1039–1042 (2002).

  9. 9

    Lees, K. R. et al. Glycine antagonist (gavestinel) in neuroprotection (GAIN International) in patients with acute stroke: a randomised controlled trial. GAIN International Investigators. Lancet 355, 1949–1954 (2000).

  10. 10

    Sacco, R. L. et al. Glycine antagonist in neuroprotection for patients with acute stroke: GAIN Americas: a randomized controlled trial. JAMA 285, 1719–1728 (2001).

  11. 11

    Kemp, J. A., Kew, J. N. & Gill, D. L. in Handbook of Experimental Pharmacology (eds. Jonas, P. & Monyer, H.) 495–527 (Springer, Berlin, 1999).

  12. 12

    Seif el Nasr, M., Perucher, B., Rossberg, C., Mennel, H. -D. & Krieglstein, J. Neuroprotective effect of memantine demonstrated in vivo and in vitro. Eur. J Pharmacol. 185, 19–24 (1990).

  13. 13

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

  14. 14

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

  15. 15

    Chen, H. -S. V. et al. Open-channel block of NMDA responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity. J. Neurosci. 12, 4427–4436 (1992). This was the first report of the molecular mechanism of memantine action (uncompetitive antagonism via open-channel block with a relatively fast off-rate from the channel) and how this mechanism could account for memantine as the first clinically tolerated NMDAR antagonist.

  16. 16

    Chen, H. -S. V. et al. Neuroprotective concentrations of the NMDA open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or LTP. Neuroscience 86, 1121–1132 (1998). This seminal publication was the first to report that memantine relatively spared synaptic NMDAR-mediated activity while blocking excessive (extrasynaptic) activity, thus predominantly accounting for the drug's clincally tolerated action.

  17. 17

    Reisberg, B. et al. Memantine in moderate-to-severe Alzheimer's disease. N. Engl. J. Med. 348, 1333–1341 (2003). This was the first randomized, placebo-controlled, multi-centre, phase III clinical trial to show the effectiveness of memantine for moderate-to severe Alzheimer's disease.

  18. 18

    Orgogozo, J. M., Rigaud, A. S., Stoffler, A., Mobius, H. J. & 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).

  19. 19

    Lucas, D. R. & Newhouse, J. P. The toxic effect of sodium L-glutamate on the inner layers of the retina. Arch. Ophathalmol. 58, 193–201 (1957). This was the first report that glutamate could be toxic to neurons in the central nervous system.

  20. 20

    Olney, J. W. Glutamate-induced retinal degeneration in neonatal mice. Electron microscopy of the acutely evolving lesion. J. Neuropathol. Exp. Neurol. 28, 455–474 (1969).

  21. 21

    Olney, J. W. & Ho, O. L. Brain damage in infant mice following oral intake of glutamate, aspartate or cysteine. Nature 227, 609–611 (1970).

  22. 22

    Lipton, S. A. Molecular mechanisms of trauma-induced neuronal degeneration. Curr. Opin. Neurol. Neurosurg. 6, 588–596 (1993).

  23. 23

    Ankarcrona, M. et al. Glutamate-induced neuronal death: A succession of necrosis or apoptosis depending on mitochondrial function. Neuron 15, 961–973 (1995).

  24. 24

    Bonfoco, E., Krainc, D., Ankarcrona, M., Nicotera, P. & Lipton, S. A. 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).

  25. 25

    Dreyer, E. B., Zhang, D. & Lipton, S. A. Transciptional or translational inhibition blocks low dose NMDA-mediated cell death. NeuroReport 6, 942–944 (1995).

  26. 26

    Quigley, H. A. et al. Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest. Ophthalmol. Vis. Sci. 36, 774–786 (1995).

  27. 27

    Vorwerk, C. K. et al. Chronic low dose glutamate is toxic to retinal ganglion cells: toxicity blocked by memantine. Invest. Ophthalmol. Vis. Sci. 37, 1618–1624 (1996).

  28. 28

    Dreyer, E. B. & Grosskreutz, C. L. Excitatory mechanisms in retinal ganglion cell death in primary open angle glaucoma (POAG). Clin. Neurosci. 4, 270–273 (1997).

  29. 29

    Dreyer, E. B. & Lipton, S. A. New perspectives on glaucoma. JAMA 281, 306–308 (1999).

  30. 30

    Naskar, R., Vorwerk, C. K. & Dreyer, E. B. Saving the nerve from glaucoma: memantine to caspaces. Semin. Ophthalmol. 14, 152–158 (1999).

  31. 31

    Berliocchi, L. et al. Botulinum neurotoxin C initiates two different programs for neurite degeneration and neuronal apoptosis. J. Cell Biol. 168, 607–618 (2005).

  32. 32

    Garden, G. A. et al. Caspase cascades in human immunodeficiency virus-associated neurodegeneration. J. Neurosci. 22, 4015–4024 (2002).

  33. 33

    Dawson, V. L., Dawson, T. M., London, E. D., Bredt, D. S. & Snyder, S. H. Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures. Proc. Natl Acad. Sci. USA 88, 6368–6371 (1991). This pioneering publication was the first to report that nitric oxide could contribute to NMDAR-mediated neurotoxcity.

  34. 34

    Dawson, V. L., Dawson, T. M., Bartley, D. A., Uhl, G. R. & Snyder, S. H. Mechanisms of nitric oxide-mediated neurotoxicity in primary brain cultures. J. Neurosci. 13, 2651–2661 (1993).

  35. 35

    Lipton, S. A. et al. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 364, 626–632 (1993). This was the first publication to report that nitric oxide could either injure or protect neurons depending on the details of its chemical redox reactions.

  36. 36

    Tenneti, L., D'Emilia, D. M., Troy, C. M. & Lipton, S. A. Role of caspases in N-methyl-D-aspartate-induced apoptosis of cerebrocortical neurons. J. Neurochem. 71, 946–959 (1998).

  37. 37

    Yun, H. -Y., Gonzalez-Zulueta, M., Dawson, V. L. & Dawson, T. M. Nitric oxide mediates N-methyl-D-aspartate receptor-induced activation of p21ras. Proc. Natl Acad. Sci. USA 95, 5773–5778 (1998).

  38. 38

    Budd, S. L., Tenneti, L., Lishnak, T. & Lipton, S. A. Mitochondrial and extramitochondrial apoptotic signaling pathways in cerebrocortical neurons. Proc. Natl Acad. Sci. USA 97, 6161–6166 (2000).

  39. 39

    Okamoto, S. et al. Dominant-interfering forms of MEF2 generated by caspase cleavage contribute to NMDA-induced neuronal apoptosis. Proc. Natl Acad. Sci. USA 99, 3974–3979 (2002).

  40. 40

    Wang, H. et al. Apoptosis-inducing factor substitutes for caspase executioners in NMDA-triggered excitotoxic neuronal death. J. Neurosci. 24, 10963–10973 (2004).

  41. 41

    Hara, M. R. et al. S-nitrosylated GAPDH initiates apoptotic cell death by nuclear translocation following Siah1 binding. Nature Cell. Biol. 7, 665–674 (2005).

  42. 42

    Johnson, J. W. & Ascher, P. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 325, 529–531 (1987).

  43. 43

    Shleper, M., Kartvelishvily, E. & Wolosker, H. D-serine is the dominant endogenous coagonist for NMDA receptor neurotoxicity in organotypic hippocampal slices. J. Neurosci. 25, 9413–9417 (2005).

  44. 44

    Mothet, J. P. et al. D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc. Natl Acad. Sci. USA 97, 4926–4931 (2000).

  45. 45

    Wolosker, H., Blackshaw, S. & Snyder, S. H. Serine racemase: a glial enzyme synthesizing D-serine to regulate glutamate-N-methyl-D-aspartate neurotransmission. Proc. Natl Acad. Sci. USA 96, 13409–13414 (1999).

  46. 46

    McBain, C. J. & Mayer, M. L. N-Methyl-D-aspartic acid receptor structure and function. Physiol. Rev. 74, 723–760 (1994).

  47. 47

    Lipton, S. A. et al. Cysteine regulation of protein function — as exemplified by NMDA-receptor modulation. Trends Neurosci. 25, 474–480 (2002).

  48. 48

    Koroshetz, W. J. & Moskowitz, M. A. Emerging treatments for stroke in humans. Trends Pharmacol. Sci. 17, 227–233 (1996).

  49. 49

    Hickenbottom, S. L. & Grotta, J. Neuroprotective therapy. Semin. Neurol. 18, 485–492 (1998).

  50. 50

    Lutsep, H. L. & Clark, W. M. Neuroprotection in acute ischaemic stroke. Current status and future potential. Drugs R & D 1, 3–8 (1999).

  51. 51

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

  52. 52

    Palmer, G. C. Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies. Curr. Drug Targets 2, 241–271 (2001).

  53. 53

    Chen, H. -S. V. & Lipton, S. A. Pharmacological implications of two distinct mechanisms of interaction of memantine with NMDA-gated channels. J. Pharmacol. Exp. Ther. 314, 961–971 (2005).

  54. 54

    Bormann, J. Memantine is a potent blocker of N-methyl-D-aspartate (NMDA) receptor channels. Eur. J. Pharmacol. 166, 591–592 (1989). This was the first paper suggesting that memantine might act at the NMDA receptor.

  55. 55

    Bresink, I. et al. Effects of memantine on recombinant rat NMDA receptors expressed in HEK 293 cells. Br. J. Pharmacol 119, 195–204 (1996).

  56. 56

    Chen, H. -S. V. & Lipton, S. A. in Post Genomic Drug Discovery Research (ed. Huang, Z.) (John Wiley & Sons, Hoboken, NJ (in the press).

  57. 57

    Blanpied, T. A., Boekman, F. A., Aizenman, E. & Johnson, J. W. Trapping channel block of NMDA-activated responses by amantadine and memantine. J. Neurophysiol. 77, 309–323 (1997).

  58. 58

    Blanpied, T. A., Clarke, R. J. & Johnson, J. W. Amantadine inhibits NMDA receptors by accelerating channel closure during channel block. J. Neurosci. 25, 3312–3322 (2005).

  59. 59

    Sobolevsky, A. I., Koshelev, S. G. & Khodorov, B. I. Interaction of memantine and amantadine with agonist-unbound NMDA-receptor channels in acutely isolated rat hippocampal neurons. J. Physiol. (Lond.) 512, 47–60 (1998).

  60. 60

    Rammes, G., Rupprecht, R., Ferrari, U., Zieglgansberger, W. & Parsons, C. G. 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. 306, 81–84 (2001).

  61. 61

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

  62. 62

    Parsons, C. G., 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).

  63. 63

    Lipton, S. A. Memantine prevents HIV coat protein-induced neuronal injury in vitro. Neurology 42, 1403–1405 (1992).

  64. 64

    Pellegrini, J. W. & Lipton, S. A. Delayed administration of memantine prevents N-methyl-D-aspartate receptor-mediated neurotoxicity. Ann. Neurol. 33, 403–407 (1993).

  65. 65

    Sucher, N. J., Lipton, S. A. & Dreyer, E. B. Molecular basis of glutamate toxicity in retinal ganglion cells. Vision Res. 37, 3483–3493 (1997).

  66. 66

    Osborne, N. N. Memantine reduces alterations to the mammalian retina, in situ, induced by ischemia. Vis. Neurosci. 16, 45–52 (1999).

  67. 67

    Navia, B. A., Yiannoutsos, C., Ellis, R., Schifitto, G., Nath, A., Shriver, S., Millar, L. & Lipton, S. A. Memantine may prevent further cognitive decline in subjects with AIDS Dementia Complex with detectable CSF HIV RNA. Neurology 64 (Suppl. 1), A247–A238 (2005).

  68. 68

    Tariot, P. N. et al. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 291, 317–324 (2004).

  69. 69

    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).

  70. 70

    Lipton, S. A. & Wang, Y. F. in Pharmacology of Cerebral Ischemia (ed. Krieglstein, J.) 183–191 (Medpharm Scientific, Stuttgart, 1996).

  71. 71

    Zurakowski, D. et al. Nitrate therapy may retard glaucomatous optic neuropathy, perhaps through modulation of glutamate receptors. Vision Res. 38, 1489–1494 (1998).

  72. 72

    Lipton, S. A., Rayudu, P. V., Choi, Y. -B., Sucher, N. J. & Chen, H. -S. V. in Prog Brain Res. (eds Mize, V., Dawson, T. M., Dawson, M. & Friedlander, M.) 73–82 (Elsevier, Amsterdam, 1998).

  73. 73

    Choi, Y. -B. et al. Molecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation. Nature Neurosci. 3, 15–21 (2000).

  74. 74

    Le, D. A. & Lipton, S. A. Potential and current use of N-methyl-D-aspartate (NMDA) receptor antagonists in diseases of aging. Drugs Aging 18, 717–724 (2001).

  75. 75

    Lipton, S. A. Concepts: turning down, but not off. Nature 428, 473 (2004).

  76. 76

    Lipton, S. A. & Chen, H. -S. Paradigm shift in neuroprotective drug development: clinically tolerated NMDA receptor inhibition by memantine. Cell Death Differ. 11, 18–20 (2004).

  77. 77

    Salter, M. & Fern, R. NMDA receptors are expressed in developing oligodendrocyte processes and mediate injury. Nature (in the press).

  78. 78

    Káradóttir, R., Cavelier, P., Bergersen, L. H. & Atwell, D. NMDA receptors in oligodendrocyte physiology and pathology. Nature (in the press).

  79. 79

    Micu, I. et al. NMDA receptors mediate Ca accumulation in central nervous system myelin during chemical ischemia. Nature (in the press).

  80. 80

    Stern-Bach, Y., Bettler, B., Hartley, M., Sheppard, P. O., O'Hara, P. J. & Heinemann, S. F. Agonist selectivity of glutamate receptors is specified by two domains structurally related to bacterial amino acid-binding proteins. Neuron 13, 1345–1357 (1994).

  81. 81

    Monyer, H. et al. Heteromeric NMDA receptors: molecular and functional distinction of subtypes. Science 256, 1217–1221 (1992).

  82. 82

    Nakanishi, S. Molecular diversity of glutamate receptors and implications for brain function. Science 258, 597–603 (1992).

  83. 83

    Meguro, H. et al. Functional characterization of a heteromeric NMDA receptor channel expressed from cloned cDNAs. Nature 357, 70–74 (1992).

  84. 84

    Kleckner, N. W. & Dingledine, R. Requirement for glycine in activation of NMDA-receptors expressed in Xenopus oocytes. Science 241, 835–837 (1988).

  85. 85

    Mayer, M. L., Westbrook, G. L. & Guthrie, P. B. Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 309, 261–263 (1984).

  86. 86

    Nowak, L., Bregestovski, P., Ascher, P., Herbet, A. & Prochiantz, A. Magnesium gates glutamate-activated channels in mouse central neurones. Nature 307, 462–465 (1984).

  87. 87

    Mori, H., Masaki, H., Yamakura, T. & Mishina, M. Identification by mutagenesis of a Mg2+-block site of the NMDA receptor channel. Nature 358, 673–675 (1992).

  88. 88

    Huettner, J. E. & Bean, B. P. Block of N-methyl-D-aspartate-activated current by the anticonvulsant MK-801: selective binding to open channels. Proc. Natl Acad. Sci. USA 85, 1307–1311 (1988).

  89. 89

    Karschin, A., Aizenman, E. & Lipton, S. A. The interaction of agonists and noncompetitive antagonists at the excitatory amino acid receptors in rat retinal ganglion cells in vitro. J. Neurosci. 8, 2895–2906 (1988).

  90. 90

    Rogawski, M. A. & Wenk, G. L. The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease. CNS Drug Rev. 9, 275–308 (2003).

  91. 91

    Selkoe, D. J. Alzheimer's disease: genes, proteins, and therapy. Physiol. Rev. 81, 741–766 (2001).

  92. 92

    Wu, P. H., Moron, M. & Barraco, R. Organic calcium channel blockers enhance [3H]purine release from rat brain cortical synaptosomes. Neurochem. Res. 9, 1019–1031 (1984).

  93. 93

    Mattson, M. P. et al. b-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity. J. Neurosci. 12, 376–389 (1992).

  94. 94

    Koh, J. Y., Yang, L. L. & Cotman, C. W. β-amyloid protein increases the vulnerability of cultured cortical neurons to excitotoxic damage. Brain Res. 533, 315–320 (1990).

  95. 95

    Topper, R. et al. Rapid appearance of b-amyloid precursor protein immunoreactivity in glial cells following excitotoxic brain injury. Acta Neuropathol. (Berl.) 89, 23–28 (1995).

  96. 96

    Harkany, T. et al. β-amyloid neurotoxicity is mediated by a glutamate-triggered excitotoxic cascade in rat nucleus basalis. Eur. J. Neurosci. 12, 2735–2745 (2000).

  97. 97

    Couratier, P. et al. Modifications of neuronal phosphorylated tau immunoreactivity induced by NMDA toxicity. Mol. Chem. Neuropathol. 27, 259–273 (1996).

  98. 98

    Miguel-Hidalgo, J. J., Alvarez, X. A., Cacabelos, R. & Quack, G. Neuroprotection by memantine against neurodegeneration induced by β-amyloid(1–40). Brain Res. 958, 210–221 (2002).

  99. 99

    Minkeviciene, R., Banerjee, P. & Tanila, H. Memantine improves spatial learning in a transgenic mouse model of Alzheimer's disease. J. Pharmacol. Exp. Ther. 311, 677–682 (2004).

  100. 100

    Li, L., Sengupta, A, Haque, N., Grundke-Iqbal, I. & Iqbal, K. Memantine inhibits and reverses the Alzheimer type abnormal hyperphosphorylation of tau and associated neurodegeneration. FEBS Lett. 566, 261–269 (2004).

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Acknowledgements

I would like to thank my colleagues for their contributions to this work, which is updated here with respect to the effects of memantine on Alzheimer's disease and vascular dementia. I am especially grateful to J. Bormann, H. -S. V. Chen, Y.-B. Choi and J. S. Stamler for their discussions or collaborations. This work was supported in part by National Institutes of Health grants.

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S.A.L. is the named inventor on a series of patents for the use of memantine for neurodegenerative disorders. When these patents were filed, Lipton was a faculty member at Harvard Medical School. Hence patents are assigned to Harvard-affiliated institutions, including Children's Hospital of Boston. In accordance with university conflict-of-interest policies, the inventor will derive no direct benefit and has no stock ownership in any company involved with memantine. He does participate in a royalty-sharing plan with the hospital, as per university guidelines, which began in early 2004 after memantine was approved by the FDA and sold for the treatment of Alzheimer's disease. The inventor has also served as a consultant to clinical studies involving memantine but did not participate in direct patient care, collection of data, or data analysis in accord with Nationa Institutes of Health conflict-of-interest guidelines.

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Amyotrophic lateral sclerosis

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Lipton, S. Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond. Nat Rev Drug Discov 5, 160–170 (2006). https://doi.org/10.1038/nrd1958

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