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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
Lipton SA.. NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics, 2004-01-01
Topic: Brain proteins, microglia and lab models
Excitotoxicity, defined as excessive exposure to the neurotransmitter glutamate or overstimulation of its membrane receptors, has been implicated as one of the key factors contributing to neuronal injury and death in a wide range of both acute and chronic neurologic disorders. Excitotoxic cell death is due, at least in part, to excessive activation of N-methyl-D-aspartate (NMDA)-type glutamate receptors and hence excessive Ca2+ influx through the receptor's associated ion channel. Physiological NMDA receptor activity, however, is also essential for normal neuronal function; potential neuroprotective agents that block virtually all NMDA receptor activity will very likely have unacceptable clinical side effects. For this reason many NMDA receptor antagonists have disappointingly failed advanced clinical trials for a number of diseases including stroke and neurodegenerative disorders such as Huntington's disease. In contrast, studies in my laboratory were the first to show that memantine, an adamantane derivative, preferentially blocks excessive NMDA receptor activity without disrupting normal activity. Memantine does this through its action as an open-channel blocker; it enters the receptor-associated ion channel preferentially when it is excessively open, and, most importantly, its off-rate is relatively fast so that it does not substantially accumulate in the channel to interfere with normal synaptic transmission. Past clinical use for other indications has demonstrated that memantine is well tolerated, and it has recently been approved in both Europe and the USA for the treatment of dementia of the Alzheimer's type. Clinical studies of the safety and efficacy of memantine for other neurological disorders, including glaucoma and other forms of dementia, are currently underway. A series of second-generation memantine derivatives are currently in development and may prove to have even greater neuroprotective properties than does memantine. These second-generation drugs take advantage of the fact that the NMDA receptor has other modulatory sites, in addition to its ion channel, that could potentially be used for safe but effective clinical intervention.
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APA 7th
Lipton, S. A. (2004). 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 : the journal of the American Society for Experimental NeuroTherapeutics. https://doi.org/10.1602/neurorx.1.1.101
Vancouver
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 : the journal of the American Society for Experimental NeuroTherapeutics. 2004. doi:10.1602/neurorx.1.1.101. PMID: 15717010.
BibTeX
@article{lipton2004-15717010,
author = {Lipton, S. A.},
title = {{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}},
journal = {NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics},
year = {2004},
doi = {10.1602/neurorx.1.1.101},
pmid = {15717010},
url = {https://doi.org/10.1602/neurorx.1.1.101}
}
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Key findings
- Past clinical use for other indications has demonstrated that memantine is well tolerated, and it has recently been approved in both Europe and the USA for the treatment of dementia of the Alzheimer's type.
Study details
- Evidence strengthLow
How this study scored 36/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multi-centre collaboration, so those were left out: it earned 21 of the 58 points we could judge it on, which is 36 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (NeuroRx : the journal of the American Society for Experimental NeuroTherapeutics) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2004 — older than 20 years, still counted |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 15717010) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 21 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 21 of the 58 points we could judge it on is 36 out of 100. |
| Total | 36 / 100 | — |
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