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Current Pharmaceutical Design


ISSN (Print): 1381-6128
ISSN (Online): 1873-4286

Review Article

NMDA Receptor Antagonists: Repositioning of Memantine as a Multitargeting Agent for Alzheimer's Therapy

Author(s): Md. Tanvir Kabir, Mohammad A. Sufian, Md. Sahab Uddin*, Mst. Marium Begum, Shammi Akhter, Ariful Islam, Bijo Mathew, Md. Siddiqul Islam, Md. Shah Amran and Ghulam Md. Ashraf*

Volume 25, Issue 33, 2019

Page: [3506 - 3518] Pages: 13

DOI: 10.2174/1381612825666191011102444

Price: $65


Alzheimer’s disease (AD) is a progressive neurodegenerative disease that causes problems with memory, thinking, and behavior. Currently, there is no drug that can reduce the pathological events of this degenerative disease but symptomatic relief is possible that can abate the disease condition. N-methyl-D-aspartate (NMDA) receptors exert a critical role for synaptic plasticity as well as transmission. Overstimulation of glutamate receptors, predominantly NMDA type, may cause excitotoxic effects on neurons and is recommended as a mechanism for neurodegeneration. Atypical activation of the NMDA receptor has been suggested for AD by synaptic dysfunction. NMDA receptor antagonists especially memantine block the NMDA receptor and can reduce the influx of calcium (Ca2+) ions into neuron, thus, toxic intracellular events are not activated. This review represents the role of NMDA receptors antagonists as potential therapeutic agents to reduce AD. Moreover, this review highlights the repositioning of memantine as a potential novel therapeutic multitargeting agent for AD.

Keywords: NMDA antagonists, memantine, glutamate receptors, amyloid beta, tau, Alzheimer’s disease.

Uddin MS, Al Mamun A, Takeda S, et al. Analyzing the chance of developing dementia among geriatric people: a cross-sectional pilot study in Bangladesh. Psychogeriatrics 2019; 19(2): 87-94.
[] [PMID: 30221441]
Ashraf GM, Uddin MS. Advances in Dementia Research. UK: IntechOpen 2019.
Alzheimer’s Association. Alzheimer’s disease facts and figures. Alzheimers Dement 2017; 13: 325-73.
Wang R, Reddy PH. Role of glutamate and NMDA receptors in Alzheimer’s disease. J Alzheimers Dis 2017; 57(4): 1041-8.
[] [PMID: 27662322]
Uddin MS, Haque A, Al Mamun A, et al. Searching the linkage between high fat diet and Alzheimer′s disease: a debatable proof stand for ketogenic diet to alleviate symptoms of alzheimer′s patient with APOE ε4 allele. J Neurol Neurophysiol 2016; 07: 1-9.
Zhang Y, Li P, Feng J, Wu M. Dysfunction of NMDA receptors in Alzheimer’s disease. Neurol Sci 2016; 37(7): 1039-47.
[] [PMID: 26971324]
Uddin MS, Nasrullah M, Hossain MS, et al. Evaluation of nootropic activity of persicaria flaccida on cognitive performance, brain antioxidant markers and acetylcholinesterase activity in rats: implication for the management of Alzheimer’s disease. Am J Psychiatry Neurosci 2016; 4: 26.
Uddin MS, Mamun A Al, Kabir MT, et al. Neurochemistry of Neurochemicals: Messengers of Brain Functions. J Intellect Disabil Diagnosis Treat 2018; 5: 137-51.
Mamum AA, Uddin MS, Wahid F, et al. Neurodefensive effect of Olea europaea L. in alloxan-induced cognitive dysfunction and brain tissue oxidative stress in mice: incredible natural nootropic. J Neurol Neurosci 2016; 7: S3.
Uddin MS, Mamun AA, Hossain MS, Akter F, Iqbal MA, Asaduzzaman M. Exploring the effect of Phyllanthus emblica L. on cognitive performance, brain antioxidant markers and acetylcholinesterase activity in rats: promising natural gift for the mitigation of Alzheimer’s disease. Ann Neurosci 2016; 23(4): 218-29.
[] [PMID: 27780989]
Uddin MS, Al Mamun A, Asaduzzaman M, et al. Spectrum of disease and prescription pattern for outpatients with neurological disorders: an empirical pilot study in Bangladesh. Ann Neurosci 2018; 25(1): 25-37.
[] [PMID: 29887680]
Alzheimer Disease International Dementia statistics: Numbers of people with dementia. Accessed on: 15 Jul 2019.
Prince M, Guerchet M, Prina M. The Global impact of dementia 2013-2050 policy brief for heads of government. Policy Br Heads Gov 2013; pp. 1-8.
Uddin MS, Al Mamun A, Iqbal MA, et al. Analyzing nootropic effect of Phyllanthus reticulatus Poir. on cognitive functions, brain antioxidant enzymes and acetylcholinesterase activity against aluminium-induced Alzheimer’s model in rats: applicable for controlling the risk factors of alzheimer’s disease. Adv Alzheimer Dis 2016; 05: 87-102.
Uddin MS, Asaduzzaman M. Neuroprotective activity of Asparagus racemosus Linn. against ethanol- induced cognitive impairment and oxidative stress in rats brain: auspicious for controlling the risk of Alzheimer’s disease. J Alzheimer’s Dis Park 2016; 6: 1-10.
Rahman A, Haque A, Uddin M, et al. In vitro screening for antioxidant and anticholinesterase effects of Uvaria littoralis Blume.: a nootropic phytotherapeutic remedy. J Intellect Disabil-Diagnosis Treat 2017; 5: 50-60.
Kabir MT, Uddin MS, Begum MM, et al. Cholinesterase inhibitors for Alzheimer’s disease: multitargeting strategy based on anti-alzheimer’s drugs repositioning. Curr Pharm Des 2019; 25: 1-17.
Cummings JL. Alzheimer’s disease. N Engl J Med 2004; 351(1): 56-67.
[] [PMID: 15229308]
Uddin MS, Al Mamun A, Hossain MS, et al. Neuroprotective effect of Phyllanthus acidus L. on learning and memory impairment in scopolamine-induced animal model of dementia and oxidative stress: natural wonder for regulating the development and progression of Alzheimer’s disease. Adv Alzheimer Dis 2016; 05: 53-72.
Hynd MR, Scott HL, Dodd PR. Differential expression of N-methyl-D-aspartate receptor NR2 isoforms in Alzheimer’s disease. J Neurochem 2004; 90(4): 913-9.
[] [PMID: 15287897]
Bamberger ME, Landreth GE. Inflammation, apoptosis, and Alzheimer’s disease. Neuroscientist 2002; 8(3): 276-83.
[] [PMID: 12061507]
Hossain MF, Uddin MS, Uddin GMS, et al. Melatonin in Alzheimer’s disease: a latent endogenous regulator of neurogenesis to mitigate alzheimer’s neuropathology. Mol Neurobiol 2019; 1-22.
[] [PMID: 31209782]
Uddin MS, Kabir MT, Al Mamun A, Abdel-Daim MM, Barreto GE, Ashraf GM. APOE and Alzheimer’s disease: evidence mounts that targeting APOE4 may combat Alzheimer’s pathogenesis. Mol Neurobiol 2019; 56(4): 2450-65.
[] [PMID: 30032423]
Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002; 297(5580): 353-6.
[] [PMID: 12130773]
Aisen PS, Gauthier S, Vellas B, et al. Alzhemed: a potential treatment for Alzheimer’s disease. Curr Alzheimer Res 2007; 4(4): 473-8.
[] [PMID: 17908052]
Oddo S, Caccamo A, Tran L, et al. Temporal profile of amyloid-β (Abeta) oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology. J Biol Chem 2006; 281(3): 1599-604.
[] [PMID: 16282321]
Uddin MS, Kabir MT. Oxidative stress in Alzheimer’s disease: molecular hallmarks of underlying vulnerability. In: Ashraf G, Alexiou A (eds) Biological, Diagnostic and Therapeutic Advances in Alzheimer’s Disease. Springer: Singapore 2019.
Uddin MS, Kabir MT. Emerging signal regulating potential of genistein against Alzheimer’s Disease: a promising molecule of interest. Front Cell Dev Biol 2019; 7: 1-12.
Palop JJ, Mucke L. Amyloid-β-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks. Nat Neurosci 2010; 13(7): 812-8.
[] [PMID: 20581818]
Palop JJ, Chin J, Roberson ED, et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 2007; 55(5): 697-711.
[] [PMID: 17785178]
Almeida CG, Takahashi RH, Gouras GK. Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system. J Neurosci 2006; 26(16): 4277-88.
[] [PMID: 16624948]
LaFerla FM, Green KN, Oddo S. Intracellular amyloid-β in Alzheimer’s disease. Nat Rev Neurosci 2007; 8(7): 499-509.
[] [PMID: 17551515]
Dineley KT, Bell KA, Bui D, Sweatt JD. β -Amyloid peptide activates α 7 nicotinic acetylcholine receptors expressed in Xenopus oocytes. J Biol Chem 2002; 277(28): 25056-61.
[] [PMID: 11983690]
Puzzo D, Privitera L, Leznik E, et al. Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J Neurosci 2008; 28(53): 14537-45.
[] [PMID: 19118188]
Uddin MS, Al Mamun A, Kabir MT, et al. Nootropic and anti-Alzheimer’s actions of medicinal plants: molecular insight into therapeutic potential to alleviate Alzheimer’s neuropathology. Mol Neurobiol 2019; 56(7): 4925-44.
[] [PMID: 30414087]
Uddin MS, Al Mamun A, Labu ZK, et al. Autophagic dysfunction in Alzheimer’s disease: cellular and molecular mechanistic approaches to halt Alzheimer’s pathogenesis. J Cell Physiol 2019; 234(6): 8094-112.
[] [PMID: 30362531]
Uddin MS, Stachowiak A, Mamun AA, et al. Autophagy and Alzheimer’s disease: from molecular mechanisms to therapeutic implications. Front Aging Neurosci 2018; 10: 1-18.
[] [PMID: 29441009]
Iqbal K, Alonso Adel C, Chen S, et al. Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta 2005; 1739(2-3): 198-210.
[] [PMID: 15615638]
SantaCruz K, Lewis J, Spires T, et al. Tau Suppression in a neurodegenerative mouse model improves memory function. Science (80- ) 2005; 309: 476-81.
Andorfer C, Kress Y, Espinoza M, et al. Hyperphosphorylation and aggregation of tau in mice expressing normal human tau isoforms. J Neurochem 2003; 86(3): 582-90.
[] [PMID: 12859672]
Lee HG, Perry G, Moreira PI, et al. Tau phosphorylation in Alzheimer’s disease: pathogen or protector? Trends Mol Med 2005; 11(4): 164-9.
[] [PMID: 15823754]
Roberson ED, Scearce-Levie K, Palop JJ, et al. Reducing endogenous tau ameliorates amyloid-induced deficits in an Alzheimer’s disease mouse model. Science 2007; 316: 750-4.
Berger Z, Roder H, Hanna A, et al. Accumulation of pathological tau species and memory loss in a conditional model of tauopathy. J Neurosci 2007; 27(14): 3650-62.
[] [PMID: 17409229]
Crimins JL, Rocher AB, Luebke JI. Electrophysiological changes precede morphological changes to frontal cortical pyramidal neurons in the rTg4510 mouse model of progressive tauopathy. Acta Neuropathol 2012; 124(6): 777-95.
[] [PMID: 22976049]
Rocher AB, Crimins JL, Amatrudo JM, et al. Structural and functional changes in tau mutant mice neurons are not linked to the presence of NFTs. Exp Neurol 2010; 223(2): 385-93.
[] [PMID: 19665462]
Hoover BR, Reed MN, Su J, et al. Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration. Neuron 2010; 68(6): 1067-81.
[] [PMID: 21172610]
Selkoe DJ. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav Brain Res 2008; 192(1): 106-13.
[] [PMID: 18359102]
Cerpa W, Dinamarca MC, Inestrosa NC. Structure-function implications in Alzheimer’s disease: effect of Abeta oligomers at central synapses. Curr Alzheimer Res 2008; 5(3): 233-43.
[] [PMID: 18537540]
Uddin MS, Amran MS. Handbook of Research on Critical Examinations of Neurodegenerative Disorders. Pennsylvania: IGI Global 2018.
Li S, Hong S, Shepardson NE, Walsh DM, Shankar GM, Selkoe D. Soluble oligomers of amyloid Beta protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 2009; 62(6): 788-801.
[] [PMID: 19555648]
Michaelis EK. Molecular biology of glutamate receptors in the central nervous system and their role in excitotoxicity, oxidative stress and aging. Prog Neurobiol 1998; 54(4): 369-415.
[] [PMID: 9522394]
Tai H-C, Wang BY, Serrano-Pozo A, Frosch MP, Spires-Jones TL, Hyman BT. Frequent and symmetric deposition of misfolded tau oligomers within presynaptic and postsynaptic terminals in Alzheimer’s disease. Acta Neuropathol Commun 2014; 2: 146.
[] [PMID: 25330988]
Frandemiche ML, De Seranno S, Rush T, et al. Activity-dependent tau protein translocation to excitatory synapse is disrupted by expo-sure to amyloid-beta oligomers. J Neurosci 2014; 34(17): 6084-97.
[] [PMID: 24760868]
Chabrier MA, Cheng D, Castello NA, Green KN, LaFerla FM. Synergistic effects of amyloid-beta and wild-type human tau on dendritic spine loss in a floxed double transgenic model of Alzheimer’s disease. Neurobiol Dis 2014; 64: 107-17.
[] [PMID: 24440055]
Shahani N, Subramaniam S, Wolf T, Tackenberg C, Brandt R. Tau aggregation and progressive neuronal degeneration in the absence of changes in spine density and morphology after targeted expression of Alzheimer’s disease-relevant tau constructs in organotypic hippocampal slices. J Neurosci 2006; 26(22): 6103-14.
[] [PMID: 16738255]
Tackenberg C, Brandt R. Divergent pathways mediate spine alterations and cell death induced by amyloid-beta, wild-type tau, and R406W tau. J Neurosci 2009; 29(46): 14439-50.
[] [PMID: 19923278]
Tackenberg C, Grinschgl S, Trutzel A, et al. NMDA receptor subunit composition determines beta-amyloid-induced neurodegeneration and synaptic loss. Cell Death Dis 2013; 4: e608-8.
[] [PMID: 23618906]
Moreno H, Choi S, Yu E, et al. Blocking effects of human tau on squid giant synapse transmission and its prevention by T-817 MA. Front Synaptic Neurosci 2011; 3: 3.
[] [PMID: 21629767]
Petralia RS. Distribution of extrasynaptic NMDA receptors on neurons. ScientificWorldJournal 2012; 2012: 1-11.
Piette F, Belmin J, Vincent H, et al. Masitinib as an adjunct therapy for mild-to-moderate Alzheimer’s disease: a randomised, placebo-controlled phase 2 trial. Alzheimers Res Ther 2011; 3(2): 16.
[] [PMID: 21504563]
Rush T, Buisson A. Reciprocal disruption of neuronal signaling and Aβ production mediated by extrasynaptic NMDA receptors: a downward spiral. Cell Tissue Res 2014; 356(2): 279-86.
[] [PMID: 24496511]
Bordji K, Becerril-Ortega J, Buisson A. Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease. Rev Neurosci 2011; 22(3): 285-94.
[] [PMID: 21568789]
Léveillé F, El Gaamouch F, Gouix E, et al. Neuronal viability is controlled by a functional relation between synaptic and extrasynaptic NMDA receptors. FASEB J 2008; 22(12): 4258-71.
[] [PMID: 18711223]
Rush T, Buisson A. Reciprocal disruption of neuronal signaling and Aβ production mediated by extrasynaptic NMDA receptors: a downward spiral. Cell Tissue Res 2014; 356(2): 279-86.
[] [PMID: 24496511]
Bordji K, Becerril-Ortega J, Buisson A. Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease. Rev Neurosci 2011; 22(3): 285-94.
[] [PMID: 21568789]
Léveillé F, El Gaamouch F, Gouix E, et al. Neuronal viability is controlled by a functional relation between synaptic and extrasynaptic NMDA receptors. FASEB J 2008; 22(12): 4258-71.
[] [PMID: 18711223]
Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 2013; 14(6): 383-400.
[] [PMID: 23686171]
Hardingham GE, Bading H. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 2010; 11(10): 682-96.
[] [PMID: 20842175]
Akhtar MW, Sanz-Blasco S, Dolatabadi N, et al. Elevated glucose and oligomeric β-amyloid disrupt synapses via a common pathway of aberrant protein S-nitrosylation. Nat Commun 2016; 7: 10242.
[] [PMID: 26743041]
Masters CL, Bateman R, Blennow K, Rowe CC, Sperling RA, Cummings JL. Alzheimer’s disease. Nat Rev Dis Primers 2015; 1: 15056.
[] [PMID: 27188934]
Lipton SA. The molecular basis of memantine action in Alzheimer’s disease and other neurologic disorders: low-affinity, uncompetitive antagonism. Curr Alzheimer Res 2005; 2(2): 155-65.
[] [PMID: 15974913]
Lipton SA. Pathologically activated therapeutics for neuroprotection. Nat Rev Neurosci 2007; 8(10): 803-8.
[] [PMID: 17882256]
Mayer ML, Westbrook GL, Guthrie PB. Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature 1984; 309(5965): 261-3.
[] [PMID: 6325946]
Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A. Magnesium gates glutamate-activated channels in mouse central neurones. Nature 1984; 307(5950): 462-5.
[] [PMID: 6320006]
Lynch G, Larson J, Kelso S, Barrionuevo G, Schottler F. Intracellular injections of EGTA block induction of hippocampal long-term potentiation. Nature 1983; 305(5936): 719-21.
[] [PMID: 6415483]
Traynelis SF, Wollmuth LP, McBain CJ, et al. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev 2010; 62(3): 405-96.
[] [PMID: 20716669]
Müller T, Albrecht D, Gebhardt C. Both NR2A and NR2B subunits of the NMDA receptor are critical for long-term potentiation and long-term depression in the lateral amygdala of horizontal slices of adult mice. Learn Mem 2009; 16(6): 395-405.
[] [PMID: 19474217]
MacDonald JF, Jackson MF, Beazely MA. Hippocampal long-term synaptic plasticity and signal amplification of NMDA receptors. Crit Rev Neurobiol 2006; 18(1-2): 71-84.
[] [PMID: 17725510]
Lau CG, Takeuchi K, Rodenas-Ruano A, et al. Regulation of NMDA receptor Ca2+ signalling and synaptic plasticity. Biochem Soc Trans 2009; 37(Pt 6): 1369-74.
[] [PMID: 19909278]
Paoletti P. Molecular basis of NMDA receptor functional diversity. Eur J Neurosci 2011; 33(8): 1351-65.
[] [PMID: 21395862]
Kornhuber J, Weller M. Psychotogenicity and N-methyl-D-aspartate receptor antagonism: implications for neuroprotective pharmacotherapy. Biol Psychiatry 1997; 41(2): 135-44.
[] [PMID: 9018383]
Javitt DC. Glutamate as a therapeutic target in psychiatric disorders. Mol Psychiatry 2004; 9(11): 984-997, 979.
[] [PMID: 15278097]
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(2): 137-9.
[] [PMID: 7478269]
Ellison G. The N-methyl-D-aspartate antagonists phencyclidine, ketamine and dizocilpine as both behavioral and anatomical models of the dementias. Brain Res Brain Res Rev 1995; 20(2): 250-67.
[] [PMID: 7795658]
Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 2003; 348(14): 1333-41.
[] [PMID: 12672860]
Pierson TM, Yuan H, Marsh ED, et al. PhD for the NISC Comparative Sequencing Program. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol 2014; 1(3): 190-8.
[] [PMID: 24839611]
Song X, Jensen MØ, Jogini V, et al. Mechanism of NMDA receptor channel block by MK-801 and memantine. Nature 2018; 556(7702): 515-9.
[] [PMID: 29670280]
Graham WV, Bonito-Oliva A, Sakmar TP. Update on Alzheimer’s disease therapy and prevention strategies. Annu Rev Med 2017; 68: 413-30.
[] [PMID: 28099083]
Sonkusare SK, Kaul CL, Ramarao P. Dementia of Alzheimer’s disease and other neurodegenerative disorders-memantine, a new hope. Pharmacol Res 2005; 51(1): 1-17.
[] [PMID: 15519530]
Areosa SA, Sherriff F, McShane R. Memantine for dementia. Cochrane Database Syst Rev 2005; (2): CD003154
[] [PMID: 15846650]
Johnson JW, Kotermanski SE. Mechanism of action of memantine. Curr Opin Pharmacol 2006; 6(1): 61-7.
[] [PMID: 16368266]
Tampi RR, van Dyck CH. Memantine: efficacy and safety in mild-to-severe Alzheimer’s disease. Neuropsychiatr Dis Treat 2007; 3(2): 245-58.
[] [PMID: 19300557]
Porter RHP, Greenamyre JT. Regional variations in the pharmacology of NMDA receptor channel blockers: implications for therapeutic potential. J Neurochem 1995; 64(2): 614-23.
[] [PMID: 7530291]
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(6): 735-67.
[] [PMID: 10465680]
Ametamey SM, Samnick S, Leenders KL, et al. Fluorine-18 radiolabelling, biodistribution studies and preliminary PET evaluation of a new memantine derivative for imaging the NMDA receptor. J Recept Signal Transduct Res 1999; 19(1-4): 129-41.
[] [PMID: 10071753]
Freudenthaler S, Meineke I, Schreeb KH, Boakye E, Gundert-Remy U, Gleiter CH. Influence of urine pH and urinary flow on the renal excretion of memantine. Br J Clin Pharmacol 1998; 46(6): 541-6.
[] [PMID: 9862242]
Peeters M, Maloteaux J-M, Hermans E. Distinct effects of amantadine and memantine on dopaminergic transmission in the rat striatum. Neurosci Lett 2003; 343(3): 205-9.
[] [PMID: 12770697]
Hesselink MB, Smolders H, Eilbacher B, De Boer AG, Breimer DD, Danysz W. The role of probenecid-sensitive organic acid transport in the pharmacokinetics of N-methyl-D-aspartate receptor antagonists acting at the glycine(B)-site: microdialysis and maximum electroshock seizures studies. J Pharmacol Exp Ther 1999; 290(2): 543-50.
[PMID: 10411561]
Standridge JB. Pharmacotherapeutic approaches to the treatment of Alzheimer’s disease. Clin Ther 2004; 26(5): 615-30.
[] [PMID: 15220008]
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(2): 135-46.
[<135:AID-GPS906>3.0.CO;2-0] [PMID: 10885864]
Peskind ER, Potkin SG, Pomara N, et al. Memantine treatment in mild to moderate Alzheimer disease: a 24-week randomized, controlled trial. Am J Geriatr Psychiatry 2006; 14(8): 704-15.
[] [PMID: 16861375]
Uddin MS, Kabir MT, Tewari D, Mathew B, Aleya L. Emerging signal regulating potential of small molecule biflavonoids to combat neuropathological insults of Alzheimer’s disease. Sci Total Environ 2019; 134836: 1-11.
Raina P, Santaguida P, Ismaila A, et al. Effectiveness of cholinesterase inhibitors and memantine for treating dementia: evidence review for a clinical practice guideline. Ann Intern Med 2008; 148(5): 379-97.
[] [PMID: 18316756]
Schneider LS, Dagerman KS, Higgins JP, McShane R. Lack of evidence for the efficacy of memantine in mild Alzheimer disease. Arch Neurol 2011; 68(8): 991-8.
[] [PMID: 21482915]
de la Monte SM, Wands JR. Alzheimer’s disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol 2008; 2(6): 1101-13.
[] [PMID: 19885299]
De Felice FG, Ferreira ST. Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease. Diabetes 2014; 63(7): 2262-72.
[] [PMID: 24931033]
Zhao H, Alam A, San C-Y, et al. Molecular mechanisms of brain-derived neurotrophic factor in neuro-protection: Recent developments. Brain Res 2017; 1665: 1-21.
[] [PMID: 28396009]
Marquard J, Otter S, Welters A, et al. Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. Nat Med 2015; 21(4): 363-72.
[] [PMID: 25774850]
Marquard J, Stirban A, Schliess F, et al. Effects of dextromethorphan as add-on to sitagliptin on blood glucose and serum insulin concentrations in individuals with type 2 diabetes mellitus: a randomized, placebo-controlled, double-blinded, multiple crossover, single-dose clinical trial. Diabetes Obes Metab 2016; 18(1): 100-3.
[] [PMID: 26362564]
Kullmann S, Heni M, Hallschmid M, Fritsche A, Preissl H, Häring HU. Brain insulin resistance at the crossroads of metabolic and cognitive disorders in humans. Physiol Rev 2016; 96(4): 1169-209.
[] [PMID: 27489306]
Bedse G, Di Domenico F, Serviddio G, Cassano T. Aberrant insulin signaling in Alzheimer’s disease: current knowledge. Front Neurosci 2015; 9: 204.
[] [PMID: 26136647]
Mosconi L. Glucose metabolism in normal aging and Alzheimer's disease: Methodological and physiological considerations for PET studies. Clin Transl Imaging 2013; 1(4): 1-25.1007/s40336-013- 0026-y.
Marquard J, Otter S, Welters A, et al. Characterization of pancreatic NMDA receptors as possible drug targets for diabetes treatment. Nat Med 2015; 21(4): 363-72.
[] [PMID: 25774850]
Marquard J, Stirban A, Schliess F, et al. Effects of dextromethorphan as add-on to sitagliptin on blood glucose and serum insulin concentrations in individuals with type 2 diabetes mellitus: a randomized, placebo-controlled, double-blinded, multiple crossover, single-dose clinical trial. Diabetes Obes Metab 2016; 18(1): 100-3.
[] [PMID: 26362564]
Clarke JR, Lyra E, Silva NM, Figueiredo CP, et al. Alzheimer-associated Aβ oligomers impact the central nervous system to induce peripheral metabolic deregulation. EMBO Mol Med 2015; 7(2): 190-210.
[] [PMID: 25617315]
Welters A, Lammert E, Mayatepek E, Meissner T. Need for better diabetes treatment: the therapeutic potential of NMDA receptor antagonists. Klin Padiatr 2017; 229(1): 14-20.
[] [PMID: 27975343]
Wollheim CB, Maechler P. Beta cell glutamate receptor antagonists: novel oral antidiabetic drugs? Nat Med 2015; 21(4): 310-1.
[] [PMID: 25849270]
Ettcheto M, Sánchez-López E, Gómez-Mínguez Y, et al. Peripheral and central effects of memantine in a mixed preclinical mice model of obesity and familial Alzheimer’s disease. Mol Neurobiol 2018; 55(9): 7327-39.
[] [PMID: 29404958]
Lipton SA. 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. NeuroRx 2004; 1(1): 101-10.
[] [PMID: 15717010]
Zurakowski D, Vorwerk CK, Gorla M, et al. Nitrate therapy may retard glaucomatous optic neuropathy, perhaps through modulation of glutamate receptors. Vision Res 1998; 38(10): 1489-94.
[] [PMID: 9667013]
Lipton SA, Choi Y-B, Takahashi H, et al. Cysteine regulation of protein function-as exemplified by NMDA-receptor modulation. Trends Neurosci 2002; 25(9): 474-80.
[] [PMID: 12183209]
Lipton SA, Rayudu PV, Choi YB, Sucher NJ, Chen HS. Redox modulation of the NMDA receptor by NO-related species. Prog Brain Res . 1998; 118: pp. 73-82.
[] [PMID: 9932435]
Choi Y-B, Tenneti L, Le DA, et al. Molecular basis of NMDA receptor-coupled ion channel modulation by S-nitrosylation. Nat Neurosci 2000; 3(1): 15-21.
[] [PMID: 10607390]
Lipton SA, Choi Y-B, Pan Z-H, et al. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature 1993; 364(6438): 626-32.
[] [PMID: 8394509]
López-Iglesias B, Pérez C, Morales-García JA, et al. New melatonin-N,N-dibenzyl(N-methyl)amine hybrids: potent neurogenic agents with antioxidant, cholinergic, and neuroprotective properties as innovative drugs for Alzheimer’s disease. J Med Chem 2014; 57(9): 3773-85.
[] [PMID: 24738476]
Yamaguchi Y, Takeda K, Hino M. Combination effects of ZSET1446/ST101 with memantine on cognitive function and extracellular acetylcholine in the hippocampus. J Pharmacol Sci 2013; 123(4): 347-55.
[] [PMID: 24292380]
Brem A-K, Atkinson NJ, Seligson EE, Pascual-Leone A. Differential pharmacological effects on brain reactivity and plasticity in Alzheimer’s disease. Front Psychiatry 2013; 4: 124.
[] [PMID: 24109459]
Mattace-Raso F. Is memantine+acetylcholinesterase inhibitor treatment superior to either therapy alone in Alzheimer’s disease? J Alzheimers Dis 2014; 41(2): 641-2.
[] [PMID: 24748117]
Lopes JP, Tarozzo G, Reggiani A, Piomelli D, Cavalli A. Galantamine potentiates the neuroprotective effect of memantine against NMDA-induced excitotoxicity. Brain Behav 2013; 3(2): 67-74.
[] [PMID: 23532860]
Hamuro A. Combination therapy with galantamine and memantine improves behavioral and psychological symptoms of dementia (BPSD) in patients with early-onset Alzheimer’s disease. Aust N Z J Psychiatry 2013; 47(6): 583-3.
[] [PMID: 23093052]
Howard R, McShane R, Lindesay J, et al. Donepezil and memantine for moderate-to-severe Alzheimer’s disease. N Engl J Med 2012; 366(10): 893-903.
[] [PMID: 22397651]
Molino I, Colucci L, Fasanaro AM, Traini E, Amenta F. Efficacy of memantine, donepezil, or their association in moderate-severe Alzheimer’s disease: a review of clinical trials. ScientificWorldJournal 2013; 2013925702
[] [PMID: 24288512]
Gareri P, Putignano D, Castagna A, et al. Retrospective study on the benefits of combined Memantine and cholinEsterase inhibitor treatMent in AGEd Patients affected with Alzheimer’s Disease: the MEMAGE study. J Alzheimers Dis 2014; 41(2): 633-40.
[] [PMID: 24643135]
Simoni E, Daniele S, Bottegoni G, et al. Combining galantamine and memantine in multitargeted, new chemical entities potentially useful in Alzheimer’s disease. J Med Chem 2012; 55(22): 9708-21.
[] [PMID: 23033965]
Fornasari E, Marinelli L, Di Stefano A, et al. Synthesis and antioxidant properties of novel memantine derivatives. Cent Nerv Syst Agents Med Chem 2017; 17(2): 123-8.
[] [PMID: 27356627]
Sestito S, Daniele S, Pietrobono D, et al. Memantine prodrug as a new agent for Alzheimer’s Disease. Sci Rep 2019; 9(1): 4612.
[] [PMID: 30874573]

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