11.28.2004

Newsweek-MSNBC Focus on Memory Enhancement
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Here is a useful survey of some of the leading candidates for successful development of memory enhancers, pills where researchers are striving to enhance cognitive performance, inluding some discussion of well-known natural compounds such as Gingko Biloba. Lastly, cognitive exercise is covered, having the benefit of being non-chemical in nature. As in all cases, early detection appears to be the key to effective prevention and treatment.


Newsweek/MSNBC-Mary Carmichael

With new insight into the mechanisms that help keep your brain sharp, neurological researchers move closer to improving your recall with a 'memory pill'

To say that Aplysia Californicus is one of nature's least glamorous beasts would be too kind. A hermaphroditic marine snail with mottled purple skin, it keeps to itself, responding to disturbances by emitting a murky fluid that stains the water around it. Its "brain," if you can call it that, is stunningly simple, with only a few thousand oversize neurons. It is not, in short, a likely candidate for glory in the animal kingdom. But a few years from now, much of the baby-boom generation may be greatly indebted to this unprepossessing little creature. Aplysia may look homely, but to scientists hoping to develop memory-enhancing medicine, it is a thing of beauty.

Thanks to the neurological research of Nobel laureate Eric Kandel and others, Aplysia's minimal nervous system is helping scientists to make sense of how memory works on the biochemical level. The molecules of memory in sea slugs, it turns out, aren't that different from some of those in humans. They are now one of the many inspirations for drugs that may someday ward off the forgetfulness that plagues so many people as they grow older. As Americans' average age creeps upward, the search for medicines that will keep them sharp is accelerating. "We're all very, very avidly grinding up cells trying to get at the molecules," says Dr. Scott Small of Columbia University Medical Center.

No pill to improve memory, aside from alternative remedies of dubious effectiveness, is currently on the market. But several small biotech companies are launching drugs grounded in the latest research, with a few already in the early stages of clinical trials that could be finished in as little as "two years, if we're lucky," says Kandel, who is now at CUMC and the Howard Hughes Medical Institute. Some of the most promising candidates have their roots in Aplysia studies. Others take their cues from even more improbable sources like the molecular consequences of smoking, focusing on some of the same receptors that nicotine targets. (Who knew it had benefits?) "These are very exciting times for treating memory loss," says Steven Siegelbaum, a neuroscientist at CUMC and HHMI. And with trials soon to yield results, they're about to get even more exciting.

It has been a long, hard slog to reach this point. Scientists now know that the brain-relying on chemical cascades kicked off by neurotransmitters-first stores short-term information in the prefrontal cortex and then transforms selected bits into long-term memories via the hippocampus, a sea-horse-shaped region tucked deep in the folds of the temporal lobe above the ear. Even such fundamental knowledge was unthinkable some 30 years ago. The concept of memory is so complex that many midcentury researchers shied away from studying it, claiming any attempt would be an example of futile reductionism. Little progress was made before 1953, when one of medicine's more famous patients arrived on the scene. An epileptic, H.M. suffered intractable, frequent seizures until he had both of his temporal lobes removed. Now deprived of his hippocampus, H.M., like the protagonists of the movies "Memento" and "50 First Dates," was unable to form new memories of people, places or things.

The unfortunate patient's case clearly signaled that the hippocampus played a central role in memory formation. But two more decades would go by before researchers figured out why or how. "The biology of memory storage was really a black hole," says Kandel. "We knew very little about it 25 years ago." Kandel's idea-to use a deceptively simple organism to solve a complex problem-met with skepticism. No wonder, says Siegelbaum, a longtime collaborator of Kandel's: "Most people were working on very basic problems. It was sort of an audacious goal at the time."

But audacious goals often drive equally audacious science, and Kandel, working with his sea snails, was on to something. Because the snails had such large neurons, and so few of them, Kandel was able to identify the individual nerve cells responsible for specific behaviors. Those nerve cells appeared to rely on some of the same biochemical processes that power the brains of more-advanced animals. Aplysia californicus turned out to be a good model for molecular memory processes in humans. Both species rely on the neural messenger cyclic AMP, which modulates a protein called CREB that can turn genes on or off. CREB is the brain's sculptor: it forms memories by reshaping the synapses, or spaces between neurons. So changes in cyclic AMP levels-and corresponding changes in CREB levels-affect the brain's ability to remodel its synapses. Less CREB equals less memory-making ability.

The practical results of this work, as well as extensive follow-up tests in mice and rats, are several new drugs now in early development at Memory Pharmaceuticals, founded in part by Kandel in 1998. MEM1414 is the inheritor of the Aplysia findings. Cyclic AMP, the neurotransmitter that dictates CREB levels, is normally degraded in the brain by enzymes called phosphodiesterases. By inhibiting those enzymes' activity, MEM14 appears to boost CREB levels and enhance the brain's long-term memory functions; researchers hope it will enhance long-term memory in patients with age-related forgetfulness and even ward off the early stages of Alzheimer's disease, even though the two ailments are not related. There's also MEM1917, a drug similar to 1414; MEM1003, which protects neurons from damaging overloads of calcium, and MEM3454, a schizophrenia treatment that targets a receptor also known to respond to nicotine. Researchers think that some schizophrenics ease their symptoms, including loss of memory function, by self-medicating with cigarettes.

Other companies are also in the hunt. Helicon has a phosphodiesterase inhibitor of its own. Sention, cofounded by Mark Bear of the Picower Center for Learning and Memory at MIT, has gone chemically "upstream" of cyclic AMP and CREB, modulating the neurotransmitters that direct the synthesis of proteins the brain uses as the basic building blocks of memory. Its intriguing new drug, C105 (which is largely under wraps for now), is in phase II trials. Cortex Pharmaceuticals, one of the oldest memory-booster firms, is focusing elsewhere, on molecules called ampakines, which modulate "AMPA receptors" in the brain that can strengthen the synapses. The company already has one drug, CX516, through phase II trials, although it is too weak to be a practical prescription option. A revved-up version, CX717, is in the works, and several other companies are also developing their own ampakines.


Researchers are reluctant to sing the praises of any of these drugs just yet. A broad class of drugs called nootropics showed potential in the 1970s, but they were "shots in the dark," says Small, and they have since fallen out of favor with mainstream scientists. Rolipram, a drug originally intended to treat depression, works in much the same way the new phosphodiesterase inhibitors do. But its nasty side effects - patients inevitably throw up after taking it-have made it an impractical solution, and although still on the market, it is not indicated for memory boosting.

Alternative medicine has also offered remedies. Ginkgo biloba, the most well known, has been a favorite for centuries. But science has been unable to verify its effectiveness, and supplements sold over the counter are often coy about their contents; even if ginkgo does work, some pill versions may not contain enough of it to have any effect. The workable alternatives to alternative medicine, until now, have largely been limited to dozens of books containing mental gymnastics intended to keep the brain's gears well greased. There's compelling evidence for some of them, particularly crossword puzzles. Learning a new language may also be an effective memory booster. And the old saw about fish being "brain food" is also, in some respects, true-a diet heavy in omega-3 fatty acids keeps blood vessels in the brain clear of blockages, allowing the nerve cells to function to the best of their abilities. But none of these remedies can completely halt "mild cognitive impairment" in adults; they can only slow it down.

Alternative remedies and brainteasers do have one advantage-they don't raise the troubling prospect of otherwise healthy people using the drugs for a boost, like steroids for geeks. "There's a question of whether we should be in the business of making memory boosters in the first place. Once we're in a gray area we at least need to be careful," says Small. "With people who are impaired by a subtle but real change in their brain function, we might not want to sit in judgment and say, 'No, we can't help you.' But the fact that a high-school student can't do well on the SAT-is that a disease?"

Ethics questions, no matter how valid, aren't likely to keep scientists from doing the basic research that could underlie drug development. And even if that research never turns into anything in pharmaceutical form, it still holds plenty of exciting potential for those seeking to understand how memory works. Science may have made considerable progress since the '70s, but there is still much to be learned. Siegelbaum's and Kandel's labs have stumbled on to an intriguing and heretofore unknown property of ion channels, tiny protein-based structures that can transport small charged molecules across the membranes of cells. One particular type of channel is found, among other places, in the hippocampus. Lab-created mice that lack this type of channel seem to be smarter than your average mouse, especially at typical memory-based tasks like repeated mazes. The upshot: when the hippocampal channels are in use, they appear to hinder memory. It's a startling finding that could have major implications for brain science. "Why has evolution come up with this channel and put it in this region of the brain if it impairs memory?" Siegelbaum wonders. He suspects that neurotransmitters close the channels, rendering them moot, when the brain needs to remember something, but leave them open otherwise to screen out the ephemera of everyday life, the things that just aren't important enough to remember long-term. (If you remember where you were when JFK was shot, your channels were probably closed at the time. If you don't remember what you had for lunch last Wednesday, well, maybe they were closed on your lunch break.) If Siegelbaum is right, the channels offer a tantalizing possibility: what if scientists could create a drug that would close them on command, allowing for total recall? "It's a bit of a daunting task," says Siegelbaum. But whether there's a pill at the end or not, it's still great science-and that's always an audacious goal.







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