“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.