Memantine does not influence AChE inhibition in rat brain by donepezil or rivastigmine but does with DFP and metrifonate in in vivo studies

Gupta, Ramesh C.; Dekundy, Andrzej

doi:10.1002/ddr.10422

Cited by 16 publications

(6 citation statements)

References 45 publications

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“…Memantine is an uncompetitive NMDA receptor antagonist, clinically used for the treatment of Alzheimer's disease, Parkinson's disease and spasticity (Ozsuer et al, 2005; Lipton, 2005). Memantine exerts various pharmacological effects by multiple mechanisms: (1) blockage of nicotinic acetylcholine receptor-ion channel complex (Masuo et al, 1986), (2) prevention of neural hyperexcitability (McLean et al, 1992), (3) reduced high-frequency repetitive activation of peripheral nerves (Wesemann et al, 1983) and (4) protection of AChE activity from inhibition by OP and CM insecticides, and OP nerve agents and prototype compound DFP (Gupta and Kadel, 1990; Gupta and Dettbarn, 1992; McLean et al, 1992; Gupta and Dekundy, 2005). Since memantine is able to prevent the pathogenic Ca 2+ influx caused by continuous activation by low-level glutamate, it is expected that memantine would also suppress formation ROS/RNS, depletion of high-energy phosphates, and mitochondrial/neuronal damage.…”

Section: Discussionmentioning

confidence: 99%

Protection of DFP-induced oxidative damage and neurodegeneration by antioxidants and NMDA receptor antagonist

Zaja‐Milatovic

Gupta

Aschner

et al. 2009

Toxicology and Applied Pharmacology

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103

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Prophylactic agents acutely administered in response to anticholinesterases intoxication can prevent toxic symptoms, including fasciculations, seizures, convulsions and death. However, anticholinesterases also have long-term unknown pathophysiological effects, making rational prophylaxis/treatment problematic. Increasing evidence suggests that in addition to excessive cholinergic stimulation, organophosphate compounds such as diisopropylphosphorofluoridate (DFP) induce activation of glutamatergic neurons, generation of reactive oxygen (ROS) and nitrogen species (RNS), leading to neurodegeneration. The present study investigated multiple affectors of DFP exposure critical to cerebral oxidative damage and whether antioxidants and NMDA receptor antagonist memantine provide neuroprotection by preventing DFP-induced biochemical and morphometric changes in rat brain. Rats treated acutely with DFP (1.25 mg/kg, s.c.) developed onset of toxicity signs within 7-15 min that progressed to maximal severity of seizures and fasciculations within 60 min. At this time point, DFP caused significant (p<0.01) increases in biomarkers of ROS (F 2 -isoprostanes, F 2 -IsoPs; and F 4 -neuroprostanes, F 4 -NeuroPs), RNS (citrulline), and declines in high-energy phosphates (HEP) in rat cerebrum. At the same time, quantitative morphometric analysis of pyramidal neurons of the hippocampal CA1 region revealed significant (p<0.01) reductions in dendritic lengths and spine density. When rats were pretreated with the antioxidants N-tert-butyl-α-phenylnitrone (PBN, 200 mg/kg, i.p.), or vitamin E (100 mg/kg, i.p./day for 3 days), or memantine (18 mg/kg, i.p.), significant attenuations in DFP-induced increases in F 2 -IsoPs, F 4 -NeuroPs, citrulline, and depletion of HEP were noted. Furthermore, attenuation in oxidative damage following antioxidants or memantine pretreatment was accompanied by rescue from dendritic degeneration of pyramidal neurons in the CA1 hippocampal area. These findings closely associated DFP-induced lipid peroxidation with dendritic degeneration of pyramidal neurons in the CA1 hippocampal area and point to possible interventions to limit oxidative injury and dendritic degeneration induced by anticholinesterase neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

Protection of DFP-induced oxidative damage and neurodegeneration by antioxidants and NMDA receptor antagonist

Zaja‐Milatovic

Gupta

Aschner

et al. 2009

Toxicology and Applied Pharmacology

Self Cite

103

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“…It has been shown in vitro that memantine does not attenuate the effects of AChE inhibitors used clinically in AD such as donepezil, tacrine or galanthamine, in contrast to clear attenuation of irreversible inhibition by DFP [ 291 ]. In an in vivo study, memantine (10mg/kg) did not inhibit AChE in any brain areas and did not interact with donepezil and rivastigmine [ 92 ]. This lack of negative interaction is also supported by recent studies investigating AChE activity in man and in clinical studies focusing on symptomatic effects [ 59a , 67 , 207 ].…”

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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“…Importantly, investigations in vitro, in vivo and ex vivo have shown that memantine does not attenuate the AChE blockade produced by therapeutically relevant concentrations of clinically used AChEIs (Enz and Gentsch 2004; Gupta and Dekundy 2005; Wenk et al 2000). …”

Section: Introductionmentioning

confidence: 99%

Memantine and Cholinesterase Inhibitors: Complementary Mechanisms in the Treatment of Alzheimer’s Disease

et al. 2013

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This review describes the preclinical mechanisms that may underlie the increased therapeutic benefit of combination therapy—with the N-methyl-d-aspartate receptor antagonist, memantine, and an acetylcholinesterase inhibitor (AChEI)—for the treatment of Alzheimer’s disease (AD). Memantine, and the AChEIs target two different aspects of AD pathology. Both drug types have shown significant efficacy as monotherapies for the treatment of AD. Furthermore, clinical observations indicate that their complementary mechanisms offer superior benefit as combination therapy. Based on the available literature, the authors have considered the preclinical mechanisms that could underlie such a combined approach. Memantine addresses dysfunction in glutamatergic transmission, while the AChEIs serve to increase pathologically lowered levels of the neurotransmitter acetylcholine. In addition, preclinical studies have shown that memantine has neuroprotective effects, acting to prevent glutamatergic over-stimulation and the resulting neurotoxicity. Interrelations between the glutamatergic and cholinergic pathways in regions of the brain that control learning and memory mean that combination treatment has the potential for a complex influence on disease pathology. Moreover, studies in animal models have shown that the combined use of memantine and the AChEIs can produce greater improvements in measures of memory than either treatment alone. As an effective approach in the clinical setting, combination therapy with memantine and an AChEI has been a welcome advance for the treatment of patients with AD. Preclinical data have shown how these drugs act via two different, but interconnected, pathological pathways, and that their complementary activity may produce greater effects than either drug individually.

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Memantine does not influence AChE inhibition in rat brain by donepezil or rivastigmine but does with DFP and metrifonate in in vivo studies

Cited by 16 publications

References 45 publications

Protection of DFP-induced oxidative damage and neurodegeneration by antioxidants and NMDA receptor antagonist

Protection of DFP-induced oxidative damage and neurodegeneration by antioxidants and NMDA receptor antagonist

Pharmacodynamics of Memantine: An Update

Memantine and Cholinesterase Inhibitors: Complementary Mechanisms in the Treatment of Alzheimer’s Disease

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