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Experimental Drug Preserves Memory in Rodents

A new compound prevents age-related memory loss by blocking part of the stress system.
October 18, 2010

An experimental drug developed by researchers at the University of Edinburgh reverses age-related memory decline in mice, returning their brains to a more youthful state of cognitive function. The compound is designed to dampen the production of glucocorticoids, stress hormones that are thought to damage the brain’s learning and memory centers over time.

“What’s most surprising is that even short-term inhibition was able to reverse memory loss in old mice,” says Jonathan Seckl, a professor of molecular medicine who was involved in the research. “I don’t think people had realized this was so reversible. It takes [the animals] back to being relatively young.”

The researchers hope to develop equivalent human therapies and are now more extensively studying the safety of a closely related compound in animals. They aim to begin human testing within a year.

Scientists have long known that glucocorticoids–a class of steroid hormones that mediate our response to stressful situations–play a role in age-related memory decline. Although short-term exposure to glucocorticoids enhances the formation of memories during stressful situations, chronically high levels of the hormones are linked to greater memory loss with age, both in humans and animals. The exact mechanism underlying this link is unclear, but researchers theorize that excess exposure to the hormones makes parts of the brain more vulnerable to damage.

Seckl and his collaborators focused on an enzyme called 11β-hydroxysteroid dehydrogenase type 1 (11 β-HSD1). This enzyme generates an active version of the key glucocorticoid hormone within brain cells and some other tissues, providing a target for fine-tuning the system without blocking the overall stress response. Tinkering with the enzyme seems to have little effect on blood levels of glucocorticoids, which are produced in the adrenal glands. Instead, “this enzyme acts as an intracellular amplifier of glucocorticoids,” says Seckl. “If you take out the amplifier, you still have stress hormones, but they shout less loudly and cause less wear and tear.”

The Edinburgh team showed that knocking out either one or both copies of the gene for this enzyme in mice preserved the animals’ memory into old age. To determine whether blocking the enzyme could improve memory in already aged animals, researchers then developed a compound designed to cross into the brain and inhibit the enzyme. Just 10 days of treatment in two-year-old mice–the maximum lifespan for a typical lab mouse–was enough to improve the animals’ performance on a test of spatial memory. The treatment “returned mice to the equivalent of when they were young and fully functioning,” says Brian Walker, another researcher involved in the study. “It’s important to emphasize that we are trying to target the pathology–the role that glucocorticoids play in age-related memory decline–not just globally improving memory.” The research was published last week in the Journal of Neuroscience.

“As a proof-of-concept study in animals, it’s fascinating,” says Bruce McEwen, a neuroscientist at Rockefeller University in New York, who was not involved in the research. “It may bring back cortisol from a level that inhibits function to a level that facilitates it.”

While it’s not yet clear how the experimental compound will affect memory in humans, some evidence suggests that drugs with a similar mechanism may be effective in older people. A drug called carbenoxolone, which inhibits the 11 β-HSD1 enzyme, among others, and which has been prescribed for stomach ulcers, improves some types of memory in both healthy older men and those with type 2 diabetes. (Type 2 diabetes, which is thought to be a risk factor for Alzheimer’s, is linked to increased glucocorticoid levels in humans.) Carbenoxolone isn’t appropriate for treating memory loss, however, Seckl says, because it has serious side effects, such as increasing blood pressure.

Researchers estimate that roughly 20 to 30 percent of people age 75 and older have elevated glucocorticoid levels (more precise figures aren’t available). Most affected is so-called declarative memory, the ability to learn new facts and remember, for example, lists. People who suffer age-related memory loss are at higher risk for developing Alzheimer’s and other forms of dementia, though the condition is not itself considered a form of dementia.

The Edinburgh compound has so far been tested only in animal models of normal aging, so scientist don’t know if the same approach would help more severe memory impairments. “Whether it would work in Alzheimer’s disease or something more aggressive, we don’t yet know,” says Seckl. His team is now studying the compound in mice that have been genetically engineered to suffer some of the symptoms of Alzheimer’s.

Previous attempts to dampen glucocorticoids’ effect on memory have had only limited success. Blocking the hormone in the blood interferes with the body’s normal stress response, and the benefits of blocking the hormone receptor appear to wear off over time, even with continued use of the drug. Most existing drugs designed to improve cognitive function, such as the Alzheimer’s drugs memantine and donepezil, act directly on neurotransmitters, chemical messengers in the brain.

The new drug may also have some beneficial side effects. Earlier animal experiments showed that blocking the enzyme in mice improves insulin sensitivity and blood sugar levels. A number of pharmaceutical companies are developing similar compounds for the treatment of type 2 diabetes.

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