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Zack Lynch is author of The Neuro Revolution: How Brain Science Is Changing Our World (St. Martin's Press, July 2009).
He is the founder and executive director of the Neurotechnology Industry Organization (NIO) and co-founder of NeuroInsights. He serves on the advisory boards of the McGovern Institute for Brain Research at MIT, the Center for Neuroeconomic Studies, Science Progress, and SocialText, a social software company. Please send newsworthy items or feedback - to Zack Lynch.
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October 23, 2003

Memory and Today's Tools

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Posted by Zack Lynch

Derek Lowe recently posted a very good explanation of the presumed mode of action of the new Alzheimer’s 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 it’s 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 don’t need to remember where you left your keys.

So a reasonable theory would be that in Alzheimer’s, 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 can’t 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.

Thanks Casey.

Comments (3) | Category: Cogniceuticals | Neuropharma


COMMENTS

1. Randall Parker on October 24, 2003 9:34 PM writes...

A very likely explanation for SSRI effects is that they stimulate neural stem cell division and differentiation.

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2. Derek Lowe on October 27, 2003 12:08 PM writes...

It's true that memantine seems to have several other modes of action (it certainly hits enough active sites to have a few!) I'm working up a follow-up piece on the drug and on NMDA in general. . .

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3. Roger Bigod on October 30, 2003 11:15 PM writes...

I take care of an aunt with AD and I've done some neuroscience research in the past, so I notice things about the disease. Phenomenologically, the traditional model of memory formation works. For example, she gets a call from a dutiful neice once a week. Usually, she can't remember the call 15 minutes later, but if she does remember, the memory will hang around a day or two. And novel events, like a visit to a doctor, register and stay around better. The theory of excessive memory formation might be testable experimentally, though.

One subtlety is the general alertness level. My aunt has a super high pain threshold, requiring a couple of Tylenol for a hip fracture. But she ran a serious hypertension with the fracture, so at some lower level of her CNS the pain registered. On Celebrex, she's much calmer and clearer. Off Celebrex, she's agitated and confused, but doesn't complain of much arthritic pain. I suspect that at 97 she has fairly bad arthritis, anddoesn't feel much pain consciously, but her CNS notices it and causes more arousal. It's way difficult to control out for this kind of effect.

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