A drug already approved by the Food and Drug Administration (FDA) to treat high blood pressure may have an equally important effect on brain function, according to new research in monkeys.
In the trial, older monkeys given the medication showed improved brain function after being given the medication. Scientists say the study may reveal what goes wrong in the prefrontal cortex, the brain region involved in the highest mental functions like abstract thought and planning, during aging, and what might be behind those “senior moments” that become more common late in life.
“It’s been known for some time that our higher cognitive functioning declines with normal aging, even beginning in middle age,” says Amy Arnsten, lead author of the study, published in the journal Nature and a professor of neurobiology at Yale University. “This is the first evidence of a cellular reason for that decline. And the hopeful and unexpected finding was that the restoration of the correct neurochemical environment actually allowed the restoration of cellular function and memory function.”
Arnsten and her colleagues studied six macaque monkeys which had been trained to remember where an object was located in space after a brief delay. Two were young adults, two were middle aged and two were older, in monkey years. Arnsten and her team recorded brain activity in certain regions of the prefrontal cortex as the monkeys performed the task.
The researchers found that nerve cells fired similarly in all of the monkeys when they first saw the object location that they had to remember. However, during the delay period—when they had to hold the object in memory—the amount of firing declined, and the amount of decline was directly correlated with age. The younger monkeys maintained more activity during this holding period than the older ones. Because monkeys do not suffer from Alzheimer’s disease or other dementias, the researchers knew that the changes seen in the older monkeys were related to ordinary aging.
With aging, the number of alpha2 receptors for a brain chemical called norepinephrine starts to drop. Norepinephrine is important for attention and memory and the alpha2 receptors also inhibit production of another brain chemical called cyclic-AMP (cAMP). Too much cAMP in the prefrontal cortex, or higher learning centers, affects the brain cells’ ability to send signals to other cells—and if they can’t fire, they can’t hold the relevant information in memory.
“Our data suggests that with the normal aging process [the brain is] having an inappropriate build up of cAMP. You don’t have enough alpha2 stimulation to inhibit it and so you have weaker network firing,” says Arnsten.
However, when researchers gave the monkeys a drug called guanfacine, which activates alpha2 receptors, firing rates normalized and the differences between the older and younger monkeys in performance were reduced. “We were very gladdened to see how much restoration we could do by simply correcting this neurochemical imbalance,” she says.
Guanfacine, which is already on the market as a generic drug for high blood pressure, is now being tested in a clinical trial to see if it can help improve cognition in the elderly. [Those in the New Haven area interested in potentially enrolling in the trial can click here; trial number is NCT00935493]
Interestingly, intense stress has the same effect on these cells in the prefrontal cortex as aging does. “There’s a rapid release of cAMP that opens potassium channels and prefrontal cells stop firing and your mind goes blank,” Arnsten says. The changes with stress are reversible, but it’s possible that greater exposure to uncontrollable stress speeds the decline of this system with age.
Arnsten previously developed an extended-release form of guanfacine called Intuniv, which was FDA-approved for the treatment of ADHD in 2009. She receives royalties on the sales of that drug, but it is not being tested for the elderly because of differences in metabolism between adults and children that make the generic form better suited to older people. The current study also used the generic drug and did not receive drug company funding.
So could guanfacine improve cognition in people who have neither ADHD or age-related memory loss? Arnsten doesn’t think so. With norepinephrine in the prefrontal cortex, having too much can be as bad as having too little. “If you have a beautiful neuron with strong persistent firing and add guanfacine, you’ve got a ceiling effect, you can’t go past what Mother Nature perfected,” she says.
The study was published in Nature.