Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system - too little activation is bad, too much is even worse

Parsons, Chris G.; Stöffler, Albrecht; Danysz, Wojciech

doi:10.1016/j.neuropharm.2007.07.013

Cited by 597 publications

(505 citation statements)

References 213 publications

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“…Drugs such as MEM may be clinically effective in modulating abnormal or dysregulated behavior, i.e., cognitive benefit in patients with Alzheimer's disease, compared to healthy behavior (Parsons et al 2007). …”

Section: Discussionmentioning

confidence: 99%

A novel procedure for assessing the effects of drugs on satiation in baboons: effects of memantine and dexfenfluramine

2008

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Rationale-Procedures for studying the effects of medications on satiation will assist the development of obesity medications.Objectives-Develop a procedure for measuring satiation during consumption of bland and highly palatable food, and determine the effect of acute intramuscular administration of dexfenfluramine (DFEN), which increases serotonin levels, and memantine (MEM), which blocks N-methyl-Daspartate receptors.Methods-A modified progressive ratio (PR) procedure was used to track changes in reinforcing strength when a food was consumed. The response requirement increased after each reinforcement, and reinforcing strength was estimated using the breakpoint (BP), which was the last completed response cost. There was one preferred food (sweet candy) and one chow pellet PR session per week. During each session, 4 male and 4 female adult baboons experienced three 1-hr PR trials, separated by 30 min. Chow pellets were available at all other times. We examined the BP for 1 to 20 candies or chow pellets. Drug effects were examined when baboons had access to 1 and 10 candies/pellets.Results-Breakpoints for candy were greater than for pellets. Varying the pellet/candy pieces per delivery, produced an inverted U-shaped function on the first trial, i.e., maximal BP was observed for 3 items, and the BP for multiple items, but not a single item, decreased across trials, i.e., BP decreased with food intake and satiation. DFEN and MEM decreased responding with the greatest effects at 10 deliveries suggesting that DFEN and MEM enhanced satiation.Conclusion-Drugs that enhance satiation for several types of food may be particularly effective for decreasing food intake.

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Section: Discussionmentioning

confidence: 99%

A novel procedure for assessing the effects of drugs on satiation in baboons: effects of memantine and dexfenfluramine

2008

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“…Memantine is an uncompetitive, open-channel blocker with strong voltage dependency and a relatively rapid off-rate from the channel (Lipton , 2006 ). To date, it is the only clinically approved NMDAR antagonist for the treatment of moderateto-severe forms of AD (2002 in Europe; in the USA) (Chen and Lipton , 2006 ;Parsons et al , 2007 ). Memantine was shown to slow the cognitive decline associated with AD after as little as 2 weeks of treatment (Johnson and Kotermanski , 2006 ).…”

Section: Targeting Extrasynaptic Nmdars To Lower a β Peptide: Interesmentioning

confidence: 99%

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

Bordji

Becerril-Ortega

2011

Revneuro

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A direct relationship has been established between synaptic activity and amyloid-β secretion. Dysregulation of neuronal calcium homeostasis was shown to increase production of amyloid-β , contributing to the initiation of Alzheimer ' s disease. Among the different routes of Ca 2 + entry, N -methyld -aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors, are especially involved in this process because of their ability to gate high levels of Ca 2 + infl ux. These receptors have been extensively studied for their crucial roles in synaptic plasticity that underlies learning and memory but also in neurotoxicity occurring during acute brain injuries and neurodegenerative diseases. For one decade, several studies provided evidence that NMDA receptor activation could have distinct consequences on neuronal fate, depending on their location. Synaptic NMDA receptor activation is neuroprotective, whereas extrasynaptic NMDA receptors trigger neuronal death and/or neurodegenerative processes. Recent data suggest that chronic activation of extrasynaptic NMDA receptors leads to a sustained neuronal amyloid-β release and could be involved in the pathogenesis of Alzheimer ' s disease. Thus, as for other neurological diseases, therapeutic targeting of extrasynaptic NMDA receptors could be a promising strategy. Following this concept, memantine, unlike other NMDA receptor antagonists was shown, to preferentially target the extrasynaptic NMDA receptor signaling pathways, while relatively sparing normal synaptic activity. This molecular mechanism could therefore explain why memantine is, to date, the only clinically approved NMDA receptor antagonist for the treatment of dementia.

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“…[153][154][155] Although the risk of cognitive impairment and psychosis tempers interest in channel blockers as a therapeutic strategy, 34,146,156 the anti-Alzheimer agent memantine has only a low risk of psychosis, because of its marked voltage-dependency and rapid kinetics 156 -158 ; its potential antidepressant actions are under investigation, although clinical data are as yet ambivalent. 159 -161 In fact, memantine interacts with several other sites 156 (Table 2), supporting the notion that NMDA receptor blockers could serve as a template for generating well-tolerated multitarget antidepressants of accelerated onset of action. Multitarget drugs could also be constructed around structures specifically blocking NR2B NMDA receptor subunits or the colocalized glycine B sites, which should have a reduced risk of psychosis and other adverse effects.…”

Section: Glutamatergic Receptors As Targets: Ionotropic and Metabotromentioning

confidence: 99%

“…However, AMPA receptors are widely distributed, play an important role in sensory transmission in the dorsal horn, and-despite promoting neurogenesis-their stimulation is implicated (possibly along with glucocorticoids) in the neurodegenerative influence of chronic stress. 148,156,164,167 It will be necessary to establish that antidepressants acting at AMPA receptors neither disrupt sensory transmission nor exacerbate deleterious neuronal effects of sustained stress. The chemical feasibility of dual AMPA facilitators/SRIs is supported by observations that the ampakines LY392,098 and LY404,187 have significant affinity for 5-HT transporters (personal observation).…”

Section: Glutamatergic Receptors As Targets: Ionotropic and Metabotromentioning

confidence: 99%

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

Millan¹

2009

Neurotherapeutics

180

123

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Summary:The past decade of efforts to find improved treatment for major depression has been dominated by genomedriven programs of rational drug discovery directed toward highly selective ligands for nonmonoaminergic agents. Selective drugs may prove beneficial for specific symptoms, for certain patient subpopulations, or both. However, network analyses of the brain and its dysfunction suggest that agents with multiple and complementary modes of action are more likely to show broad-based efficacy against core and comorbid symptoms of depression. Strategies for improved multitarget exploitation of monoaminergic mechanisms include triple inhibitors of dopamine, serotonin (5-HT) and noradrenaline reuptake, and drugs interfering with feedback actions of monoamines at inhibitory 5-HT 1A , 5-HT 1B and possibly 5-HT 5A and 5-HT 7 receptors. Specific subsets of postsynaptic 5-HT receptors mediating antidepressant actions are under study (e.g., 5-HT 4 and 5-HT 6 ). Association of a clinically characterized antidepressant mechanism with a nonmonoaminergic component of activity is an attractive strategy. For example, agomelatine (a melatonin agonist/5-HT 2C antagonist) has clinically proven activity in major depression. Dual neurokinin 1 antagonists/5-HT reuptake inhibitors (SRIs) and melanocortin 4 antagonists/SRIs should display advantages over their selective counterparts, and histamine H 3 antagonists/SRIs, GABA B antagonists/SRIs, glutamatergic/SRIs, and cholinergic agents/SRIs may counter the compromised cognitive function of depression. Finally, drugs that suppress 5-HT reuptake and blunt hypothalamo-pituitary-adrenocorticotrophic axis overdrive, or that act at intracellular proteins such as GSK-3␤, may abrogate the negative effects of chronic stress on mood and neuronal integrity. This review discusses the discovery and development of dual-and tripleacting antidepressants, focusing on novel concepts and new drugs disclosed over the last 2 to 3 years.

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Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system - too little activation is bad, too much is even worse

Cited by 597 publications

References 213 publications

A novel procedure for assessing the effects of drugs on satiation in baboons: effects of memantine and dexfenfluramine

A novel procedure for assessing the effects of drugs on satiation in baboons: effects of memantine and dexfenfluramine

Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer’s disease

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

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