Steroid Seen as a Potential Memory Aid : Medicine: Small doses administered to mice have shown effectiveness, researchers say. Trials on aging humans are planned.

A California scientist has found that a simple steroid can improve memory in mice and is planning to begin trials of the drug in aging humans with impaired memories.

The steroid, called pregnenolone, is at least several hundred times as potent as any memory enhancer that has been tested, said neurobiologist Eugene Roberts of the City of Hope Medical Center in Duarte, who performed the studies in conjunction with biologists at the St. Louis Veterans Administration Medical Center in Missouri.

They report today in the Proceedings of the National Academy of Sciences says that administration of pregnenolone apparently restores normal levels of the hormone, which decline during the aging process, and facilitates the animals’ ability to remember learned tasks.

The drug has been tested in humans as a treatment for arthritis, Roberts said, and it was found to produce no adverse effects--which should simplify the process of obtaining permission from the Food and Drug Administration for human memory tests.

Roberts did not expect such success with the drug, which he tested as part of a group of steroid hormones. “It was kind of a sleeper that really set me back on my heels,” he said in an interview. “We’re very excited about it.”

Pregnenolone is the second memory-enhancing drug that Roberts is investigating. He and neurologist Bruce Miller of UCLA--Harbor General Hospital are testing another steroid called DHEA (dehydroepiandrosterone) in 40 humans with minor memory problems. But the researchers do not know which patients are receiving DHEA and which are receiving placebos, so they do not know how well the tests are proceeding. Even if those trials are successful, Roberts said, he believes that pregnenolone will prove more effective.

Pregnenolone is produced from the metabolism of cholesterol in the body. It is then converted by intracellular machinery into all of the other steroid hormones used by males and females. But the naturally occurring form of the chemical “is not known to have any effects at all,” Roberts said.

Roberts and his colleagues, biologists James F. Flood and John E. Morley, tested pregnenolone and a variety of other steroids in groups of 15 mice trained to avoid having their feet shocked in a device called a T-maze.

The mice were placed in one end of the 1 1/2-foot-long device and trained to go rapidly into one of two boxes at the T end after a bells sounds. If they did not make it within five seconds, their feet received a mild shock until they entered the box.

The researchers trained the mice and then injected small quantities of either the steroids or a placebo into their brains. The mice would be tested again a week later to determine how well they remembered the training.

The group found that virtually all of the steroids significantly reduced the number of runs required for the mice to relearn the foot-shock avoidance after the week off from training, but that pregnenolone was effective at the lowest doses.

Roberts is particularly enthusiastic about pregnenolone because of the experience in treating humans with it. It was used in the late 1940s to treat rheumatoid arthritis but fell into disuse when researchers found that cortisone was much more effective. But pregnenolone was never found to have any adverse effects, he said.

Roberts believes that pregnenolone functions by serving as a raw material for the production of all steroid hormones that are used in storing information in memory. Concentrations of many of these steroids in the brain decline with age, he said--which may explain the rising incidence of memory problems as the body ages.

By restoring normal levels of the hormones, he postulates, the drug restores the brain to its capabilities of youth. In their tests, he noted, 1-year-old mice given the drug had the learning ability of healthy 2-month-old mice.

Pregnenolone may have other uses as well, he speculated. Although cholesterol has a beneficial role as a progenitor of steroid hormones, the accumulation of cholesterol in blood vessels is a major contributor to the development of heart disease. Some indirect evidence suggests that attempts to limit cholesterol formation correlate statistically with reduced mental sharpness.

Last year, epidemiologist Michael F. Oliver of the Wynn Institute for Metabolic Research in London summarized the results of a large number of human trials in which cholesterol-blocking agents were used in attempts to forestall heart disease. While the anti-cholesterol drugs did reduce the number of cardiac deaths in the study, those reductions were accompanied by an unexplained increase in nervous system-related phenomena such as accidents, suicides and violence.

Roberts speculated in his report that those increases in deaths may be linked to changes in the nervous system resulting from the reduced levels of cholesterol and the resulting reductions in the synthesis of steroids. That impairment might be reversed, he said, by administering pregnenolone along with the cholesterol-blocking agents.

Roberts conceded that this link is highly speculative.