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October 23, 2003
Memory and Today's Tools
Derek Lowe recently posted a very good explanation of the presumed mode of action of the new Alzheimers drug memantine.
Memantine has some affinity for a wide range of receptors in the brain, but at the doses that are seen therapeutically, the relevant interactions seems to be with the NMDA receptor....The weird thing is, memantine is an antagonist; it blocks NMDA signaling. So at high doses, it actually interferes with memory....At clinical doses, the compound does play against type and seem to improve memory. The best guess for how this works is through a mechanism for neuronal injury in Alzheimer's. Too frequent (and too prolonged) firing of excitatory pathways like NMDA have long been associated with cellular damage in the brain, and this seems to be going on in AD as well...
There is some evidence that neurons with NMDA receptors are lost in AD, but its hard to explain the improvement in cognitive performance of some patients if you are merely stopping or slowing damage. Also memantine has been shown to have a short term effect on memory and memory related cellular plasticity. Why not consider this evidence that memantine is working through a more subtle mechanism than preventing excitotoxicity?
NMDA is believed to function in learning by giving a neuron memory of previous activity. Since we have to be picky about which memories are stored and which can be forgotten, NMDA is thought to be a sort of memory bouncer determining whether the stimulus is strong enough to be laid down permanently, or whether you really dont need to remember where you left your keys.
So a reasonable theory would be that in Alzheimers, NMDA is underactive and is not letting in any new memories. But the efficacy (though slight) of memantine suggests that maybe NMDA is overactive, letting in any memory at all and promoting the cellular changes that allow memories to be stored at random. Without any barrier for memory formation, perhaps a neuron cant distinguish between important and unimportant events, so it appears that nothing is stored, when really everything is stored and each event instantly erases the last event. Memantine can reduce the activity of NMDA and restore its selectivity for the right memories.
Complicated explanations may not suit a pharmaceutical company, but understanding the true therapeutic nature of current pharmaceuticals will be an important part of future neuroceutical development. For example, SSRI's like Prozac take several weeks to be effective, but for years pharma claimed that the anitdepressant effect was due to a short term reduction in serotonin reuptake. The fact is we still don't know why SSRI's have the effect they do.
| Category: Cogniceuticals | Neuropharma
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