P.4.012 Effect of memantine on levels of the amyloid beta peptide in cell cultures

Lahiri, D.K.; Alley, G.M.; Morgan, Carlos; Banerjee, Pradeep; Farlow, Martin R.

doi:10.1016/s0924-977x(03)92207-3

Cited by 4 publications

(3 citation statements)

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“…Earlier reports point to a direct role of memantine in diminishing the production and toxicity of Aβ peptide. For instance, memantine has been shown to reduce the levels of APP, Aβ 1–40 , and Aβ 1–42 peptides in human neuroblastoma cells and in rat primary cortical neurons and to provide neuroprotection against Aβ neurotoxicity (Miguel‐Hidalgo et al, 2002; Lahiri et al, 2003a, b). Memantine treatment for as little as 10 days has been show to reduce the cortical levels of APP in AD Tg mice by 45–55% (Unger et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Memantine leads to behavioral improvement and amyloid reduction in Alzheimer's‐disease‐model transgenic mice shown as by micromagnetic resonance imaging

Scholtzova

Wadghiri

Douadi

et al. 2008

J of Neuroscience Research

109

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Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to improve learning and memory in several preclinical models of Alzheimer’s disease (AD). Memantine has also been shown to reduce the levels of amyloid β (Aβ) peptides in human neuroblastoma cells as well as to inhibit Aβ oligomer-induced synaptic loss. In this study, we assessed whether NMDA receptor inhibition by memantine in transgenic mice expressing human amyloid-beta precursor protein (APP) and presenilin 1 (PS1) is associated with cognitive benefit and amyloid burden reduction by using object recognition, micromagnetic resonance imaging (µMRI), and histology. APP/PS1 Tg mice were treated either with memantine or with vehicle for a period of 4 months starting at 3 months of age. After treatment, the mice were subjected to an object recognition test and analyzed by ex vivo µMRI, and histological examination of amyloid burden. µMRI was performed following injection with gadolinium-DTPA-Aβ1–40. We found that memantine-treated Tg mice performed the same as wild-type control mice, whereas the performance of vehicle-treated Tg mice was significantly impaired (P = 0.0081, one-way ANOVA). Compared with vehicle-treated animals, memantine-treated Tg mice had a reduced plaque burden, as determined both histologically and by µMRI. This reduction in amyloid burden correlates with an improvement in cognitive performance. Thus, our findings provide further evidence of the potential role of NMDA receptor antagonists in ameliorating AD-related pathology. In addition, our study shows, for the first time, the utility of µMRI in conjunction with gadolinium-labeled Aβ labeling agents to monitor the therapeutic response to amyloid-reducing agents.

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Section: Discussionmentioning

confidence: 99%

Memantine leads to behavioral improvement and amyloid reduction in Alzheimer's‐disease‐model transgenic mice shown as by micromagnetic resonance imaging

Scholtzova

Wadghiri

Douadi

et al. 2008

J of Neuroscience Research

109

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“…In studies in cultured human neuroblastoma (SK-N-SH) cells, treatment with memantine for 24 to 48 hours provided evidence that the drug may decrease disturbed APP processing [ 142 ]. Memantine treatment of cultured human neuroblastoma cells and primary fetal rat cortical neurons, albeit for a longer duration of 12 days, also decreased levels of Aβ 1-40 starting at a therapeutically relevant concentration of 1 µM [ 142 ].…”

Section: Primary Pharmacodynamicsmentioning

confidence: 99%

Pharmacodynamics of Memantine: An Update

Rammes¹,

Danysz²,

Parsons

2008

149

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Memantine received marketing authorization from the European Agency for the Evaluation of Medicinal Products (EMEA) for the treatment of moderately severe to severe Alzheimer´s disease (AD) in Europe on 17 th May 2002 and shortly thereafter was also approved by the FDA for use in the same indication in the USA. Memantine is a moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with strong voltage-dependency and fast kinetics. Due to this mechanism of action (MOA), there is a wealth of other possible therapeutic indications for memantine and numerous preclinical data in animal models support this assumption. This review is intended to provide an update on preclinical studies on the pharmacodynamics of memantine, with an additional focus on animal models of diseases aside from the approved indication. For most studies prior to 1999, the reader is referred to a previous review [196].In general, since 1999, considerable additional preclinical evidence has accumulated supporting the use of memantine in AD (both symptomatic and neuroprotective). In addition, there has been further confirmation of the MOA of memantine as an uncompetitive NMDA receptor antagonist and essentially no data contradicting our understanding of the benign side effect profile of memantine. THERAPEUTIC TARGETThe maximal therapeutically-relevant plasma concentration of memantine is around 1 M (see [55,203]). Brain extracellular fluid (ECF) concentration of around 0.8 M can be anticipated [102] and any receptor that expresses an affinity at, or below, the very low M range should be considered as a potential therapeutic target. Given this assumption, there are only four plausible known target types to date: the most likely is the NMDA receptor channel, but 5-hydroxy-tryptamine (5-HT 3 ) receptors [220] and 7 and/or 4 2 nicotinic receptors [11] should also be taken into consideration [11,37,165].The 7 and 4 2 nicotinic acetylcholine receptor and the 5-HT 3 receptor systems have been suggested to play a role in modulating CNS functions, including learning and memory. These receptors are structurally related, containing large extracellular ligand-binding domains and four transmembrane domains that are largely conserved. They exhibit considerable cross-pharmacology, e.g. high concentrations of the 7 nAChR agonist nicotine inhibit 5-HT 3 receptor-mediated responses, and high concentrations of the 5-HT 3 receptor agonist serotonin inhibit 7 nAChR-mediated responses. Based on this knowledge, it seems reasonable to investigate whether ligands specific for either receptor, might have affinity for both. NMDA RECEPTORS Fast Kinetics and Strong Voltage-DependencyMemantine blocks the NMDA receptor channel in an use-dependent manner, meaning that it can only gain access to the channel in the presence of agonist and remains largely *Address correspondence to this author at Preclinical R & D, Merz Pharmaceuticals, Eckenheimer Landstrasse 100, 60318 Frankfurt am Main, Germany; Tel: +49 69 1503368; E-mail: christopher.parsons@m...

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“…Lahiri et al demonstrated in cell cultures and in conditioned media of a human neuroblastoma cell line that memantine, at a nontoxic dose, decreased secreted ß-amyloid levels without altering cellular amyloid precursor protein (APP) levels, suggesting that memantine may potentially inhibit the amyloidogenic pathway. 31,32 In addition, memantine was able to restore the tau phosphatase and kinase activities and the phosphorilation/dephosphorilation imbalance associated with neurodegeneration and accumulation of tau, suggesting that this drug might be useful for treatment of AD and related tauopathies. 33,34 Glial activation has also been suggested to play a critical role in the progression of AD, although its precise mechanism is not clearly understood.…”

Section: Preclinical Studiesmentioning

confidence: 99%

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

Molinuevo¹,

Lladó²,

Rami³

2005

Am J Alzheimers Dis Other Demen

105

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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-D-aspartate (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.

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P.4.012 Effect of memantine on levels of the amyloid beta peptide in cell cultures

Cited by 4 publications

References 0 publications

Memantine leads to behavioral improvement and amyloid reduction in Alzheimer's‐disease‐model transgenic mice shown as by micromagnetic resonance imaging

Memantine leads to behavioral improvement and amyloid reduction in Alzheimer's‐disease‐model transgenic mice shown as by micromagnetic resonance imaging

Pharmacodynamics of Memantine: An Update

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

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