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 |
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Authors: | Lipton Stuart A |
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Institution: | (1) Center for Neuroscience, Aging and Stem Cell Research, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA;(2) Department of Neurosciences, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92039, USA; |
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Abstract: | 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 ofN-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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