Cortex Drug in Alzheimer's Trial at NINDS
Ampikine Compound Keeps Improving Rat Memory Even After Dosage Drops To Zero
By David N. Leff
There are some things a rat just won't do.
But under the influence of an experimental memory-enhancement drug, rodents at Wake Forest University, in Winston Salem, N. C., "learned things that rats never learn," said neuroscientist Gary Lynch.
He is co-author of a two-part, 24-page paper in the April 1, 1998 Journal of Neuroscience. Part I bears the title: "Facilitative effects of the ampikine CX516 on short-term memory in rats: Enhancement of delayed-nonmatch-to-sample [DNMS] performance."
The article's senior author is neurophysiologist Sam Deadwyler, who put cohorts of rats through two-year workouts on the DNMS memory-training system.
The action took place in a square, clear, Plexiglas chamber, 17 inches on each side and 21 inches high, with two retractable levers on each of two opposing sides. "A rat with 16 electrodes in his hippocampus, placed in this box has two choices," Lynch recounted. "He has to push down on one lever that's extended, collect his reinforcement reward, then turn around 180 degrees, poke his nose at a photoelectric cell, and wait till he gets another signal to go back."
When he turns back, the rodent confronts two levers, not one. The left lever paid off several seconds ago, but this time around he must, counter-intuitively, choose the right-hand rod. "You can imagine," Lynch observed, "this takes some training."
During the trials, half of each rat cohort received varying doses of injectable ampikine. This family of brain-cell-nurturing drugs were developed by Lynch and his colleague, chemist Gary Rogers, at the University of California at Irvine, where Lynch is a professor of neurophysiology. Nine years ago, Lynch co-founded Cortex Pharmaceuticals Inc., of Irvine, Calif., where he serves as scientific director. Cortex acquired exclusive patent rights to ampikines from the university. (See BioWorld Today, Nov. 4, 1993, p. 5.)
Cortex Drug Smartens Up Rats
"These rats," Lynch observed, "were having results better than the pros have ever seen. And the amazing part," he told BioWorld Today, "is that when Deadwyler's people stopped giving them the drug, a week later their results were still better. They were showing that repeated administration of an ampikine led to animals having a better memory, long after the drugs were gone. That's the first report of anything of the kind. It was totally unexpected."
Lynch explained that "the task the rats learned is completely hippocampally dependent. The memory decays with an absolutely stereotyped time course. You make the delay for remembering 10 seconds, it's 100 percent retained. Make it one minute, pure chance enters in."
Then, he turned from the lessons the rats mastered to what the researchers learned.
"If you're giving the rats an ampikine, and if it enhances excitatory [increased rapidity or intensity] drive on pyramidal neurons at the cortex, the hippocampus, you should be up-regulating growth factor genes, hence the process of synapse growth formation and maintenance. That's almost a prediction."
To picture this brain mechanism, Lynch postulated two alternatives:
* Option A: "Those rats took ampikines for two weeks, under conditions of intense electrical activity. Learning those levers increased excitatory drive, turned on growth-factor genes, and made their neurons healthier. They were able to do what rats never do — acquire a short-term memory beyond that of the normal rat."
* Option B: "Under the influence of that drug over that period of time, rats learn something that rats never learn. They were sufficiently smart to master a trick in that task which, once learned, is still there long after the drug is withdrawn, which allows them to become so much smarter."
If ampikines can work this wonder for the genus Rattus, what might it do for members of the Homo sapiens species who may be losing their smarts to old age, especially Alzheimer's disease (AD)?
Short-term trials of the drug in 1996 on 16 young men in Sweden and 30 elderly ones in Germany reported that ampikines improved memory scores in both groups. (See BioWorld Today, Nov. 19, 1996, p. 1.)
Clinical Trial Under Way of Ampikine in AD Patients
But Lynch points out today that those were "acute trials, with only one or two drug treatments. What we're talking about now is: What would happen if people took ampikine on a chronic basis, like Deadwyler's rat studies?"
A dozen AD patients are on such a regimen at the National Institute of Neurological Diseases and Stroke (NINDS), in Bethesda, Md.
Neurologist Thomas Chase, who chairs the Experimental Research Branch at NINDS, told BioWorld Today his institute is "more than halfway through" recruiting AD patients to test ampikine in a randomized, double-blind, dose-escalation Phase I trial that will eventually enroll a score of volunteers.
"We have high hopes that it might show something," Chase continued, "but at this point it's completely blinded, and we have no idea — no clinical data to analyze — other than that there have been no significant problems with toxicity."
Participants, Chase said, "are mild to moderately advanced patients with AD. Finding patients who are good for a trial like this is difficult, because what we're looking for are subjects who understand what we are trying to do, so there's not an informed-consent issue raised, and are not only acquiescent in participating, but interested.
"We get the pure ampikine substance from Cortex," Chase said, "but it's made into a form that we can administer orally, as pills, by the NIH [National Institutes of Health] Pharmaceutical Development Service.
"Extrapolating dose from what looks good in a rodent to what might work in a human is problematic," he observed, "so we want to be sure that we are not going to miss an effect by simply not moving ahead with the dose."
Chase is "not aware of any other human AD trial of ampikine currently under way. There's no particular point in giving it to more people at this point," he concluded. "It's relatively expensive, but free at NIH." *