Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond
@article{Lipton2006ParadigmSI, title={Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond}, author={Stuart A. Lipton}, journal={Nature Reviews Drug Discovery}, year={2006}, volume={5}, pages={160-170} }
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…
776 Citations
NEUROPROTECTIVE STRATEGIES: DEVELOPMENT OF A CLINICALLY TOLERATED COMPOUND *
- Biology
- 2007
It is demonstrated how compounds that act by an uncompetitive mechanism with a fast off-rate (socalled UFO drugs that quickly disappear from the target when no longer needed) can target pathologically active tissue.
Recent insights into the mode of action of memantine and ketamine.
- Biology, PsychologyCurrent opinion in pharmacology
- 2015
Studies on the interaction of NMDA receptor antagonist memantine with cell membranes: A mini-review.
- Biology, MedicineChemico-biological interactions
- 2018
Memantine in the treatment of Alzheimer’s disease
- Biology, Psychology
- 2006
Clinical trials have shown that memantine is generally safe and well tolerated, and have provided evidence for its efficacy as assessed by cognitive, behavioral, functional and global measures.
Pharmacologically targeted NMDA receptor antagonism by NitroMemantine for cerebrovascular disease
- BiologyScientific reports
- 2015
Novel NitroMemantines are described, comprising an adamantane moiety that binds in the NMDAR-associated ion channel that is used to target a nitro group to redox-mediated regulatory sites on the receptor and are both well tolerated and effective against cerebral infarction in rodent models.
Design, synthesis, and evaluation of polyamine-memantine hybrids as NMDA channel blockers.
- BiologyBioorganic & medicinal chemistry
- 2018
Role of nonsynaptic GluN2B-containing NMDA receptors in excitotoxicity: Evidence that fluoxetine selectively inhibits these receptors and may have neuroprotective effects
- BiologyBrain Research Bulletin
- 2013
Neuroprotective properties of memantine in different in vitro and in vivo models of excitotoxicity
- BiologyThe European journal of neuroscience
- 2006
Findings suggest that inhibition of the NMDA‐R by memantine is sufficient to block excitotoxicity, while still allowing some degree of signalling, as well as restoring the number of neurons able to migrate out of the stressed microexplants.
Is Memantine Effective as an NMDA Receptor Antagonist in Adjunctive Therapy for Schizophrenia?
- Psychology, MedicineBiomolecules
- 2020
There are numerous randomized, double-blind, placebo-controlled clinical trials showing that add-on treatment with memantine improves negative and cognitive symptoms, particularly the negative symptoms of schizophrenia, indicating that memantine as adjunctive therapy in schizophrenia helps to ameliorate negative symptoms and cognitive deficits.
In vivo evidence for functional NMDA receptor blockade by memantine in rat hippocampal neurons
- BiologyJournal of Neural Transmission
- 2010
Therapeutic doses of memantine are able to antagonize NMDA receptor-mediated activity in the principal cells of the hippocampus in vivo, i.e. in the presence of physiological concentrations of Mg2+.
References
SHOWING 1-10 OF 117 REFERENCES
Potential and Current Use of N-Methyl-D-Aspartate (NMDA) Receptor Antagonists in Diseases of Aging
- Biology, PsychologyDrugs & aging
- 2001
The evidence that clinically safer NMDA antagonists such as memantine and nitroglycerin, and the combination drug nitro-memantine, are promising as drugs in treating neurodegenerative diseases is presented.
The neuropharmacological basis for the use of memantine in the treatment of Alzheimer's disease.
- Biology, PsychologyCNS drug reviews
- 2003
Channel-level factors may allow memantine to block channel activity induced by low, tonic levels of glutamate--an action that might contribute to symptomatic improvement and could theoretically protect against weak excitotoxicity--while sparing synaptic responses required for normal behavioral functioning, cognition and memory.
Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies.
- Biology, MedicineCurrent drug targets
- 2001
This review focuses only on those competitive and use-dependent NMDA receptor antagonists that reached clinical trails and link the in vivo pharmacological investigations that led to the success/mistakes/ failures for eventual testing of promising compounds in the clinic.
Memantine is a clinically well tolerated N-methyl-d-aspartate (NMDA) receptor antagonist—a review of preclinical data
- Biology, PsychologyNeuropharmacology
- 1999
Open-channel block of N-methyl-D-aspartate (NMDA) responses by memantine: therapeutic advantage against NMDA receptor-mediated neurotoxicity
- Biology, PsychologyThe Journal of neuroscience : the official journal of the Society for Neuroscience
- 1992
Low micromolar concentrations of memantine, levels known to be tolerated by patients receiving the drug for the treatment of Parkinson's disease, prevent NMDA receptor-mediated neurotoxicity in cultures of rat cortical and retinal ganglion cell neurons; memantine also appears to be both safe and effective in a rat stroke model, suggesting that memantine has considerable therapeutic potential for the myriad of clinical entities associated with NMda receptor- mediated neurotoxicity.
Pharmacological Implications of Two Distinct Mechanisms of Interaction of Memantine with N-Methyl-d-aspartate-Gated Channels
- BiologyJournal of Pharmacology and Experimental Therapeutics
- 2005
The distinct patterns of interaction and the relative degree of affinity of memantine for these two binding sites contribute to the drug's excellent pharmacological profile of clinical tolerability and should be considered in searching for improved neuroprotective agents in this class.
Neuroprotective concentrations of the N-methyl-D-aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or long-term potentiation
- Biology, PsychologyNeuroscience
- 1998
Neuroprotection by memantine against neurodegeneration induced by β-amyloid(1–40)
- Biology, PsychologyBrain Research
- 2002
NMDA receptor pathways as drug targets
- BiologyNature Neuroscience
- 2002
The future prospects for drugs that act on NMDA receptor pathways are critically assessed, including potential treatments for some major disorders such as stroke and Alzheimer's disease, for which effective therapies are still lacking.