Memory drug studied in mice

The Daily Express reports today of a “drug to stop memory loss”. It said that a British team of researchers have made an amazing breakthrough and are a step closer to an “anti-ageing drug for the brain”.

Underpinning this news report is a study that tested a new drug in mice. The study found that mice that received the drug had better spatial memory than control mice when they were tested in a maze.

These findings do not mean that a treatment or a cure for dementia has been found. This is good research within its own right, and well documented by the researchers in their research paper. However, this is still early-stage research in animals. As there was no long-term follow-up of the animals and its effects on other types of memory, the findings have little immediate relevance to the health of people with dementia. The Daily Express’s front-page report is not justified by this research.

Where did the story come from?

The study was carried out by researchers from the University of Edinburgh and funded by the Wellcome Trust and the Medical Research Council (MRC). The research paper was published in the peer-reviewed Journal of Neuroscience .

The newspapers have over-interpreted the relevance of these findings to humans.

What kind of research was this?

The researchers say that age-related cognitive deficits in humans and rodents have been associated with long-term raised levels of the stress hormones glucocorticoids. Previous studies have indicated that keeping the levels of these hormones in the brain low may prevent these deficits. They say there are a number of chemicals in the brain responsible for regulating levels of these glucocorticoids. One in particular, called 11ß-HSD1, acts to increase levels of these hormones. Some animal studies have shown that mice that don’t produce 11ß-HSD1 have lower levels of glucocorticoids in certain parts of their brains, and they have better memory.

In this laboratory and animal research, the researchers were investigating the effects of a treatment they had developed, called UE1961, which blocked the action of the enzyme 11ß-HSD1. The theory was that it would cause reduced levels of stress hormones in the brain, thereby improving cognition.

What did the research involve?

In this study, researchers were testing the effects of a drug that could inhibit 11ß-HSD1 on cognitive health in mice.

Some of the mice were genetic mutants that lacked the ability to produce 11ß-HSD1. Researchers tested different types of mutant mice in a maze test when they were six months old. Others were tested at 24 months. The maze test assesses spatial memory in mice. It is called the Y-maze because mice are put into a Y-shaped maze, initially with one of the three arms blocked off, then with all three arms available. The amount of time the mice spent in the new, unfamiliar arm during the second assessment was used as an indicator of their spatial memory.

The part of the research most relevant to the news coverage is where the researchers tested the effects of their newly developed drug in older mice. Here, 12-month-old mice with no mutations were given some of the drug every 12 hours for three days while another group was given a control (placebo). These mice were killed and their brains examined to determine the effects of the drug on the levels of 11ß-HSD1 in their brains. In a separate part to the experiment, a different set of mice without mutations were given the drug or a placebo for 10 days before being tested in the Y-maze.

What were the basic results?

All of the mice spent more time in the new, unfamiliar arm in the Y-maze than in the arms they had already visited. When the maze test was specifically aimed at testing spatial memory (dependent on a part of the brain called the hippocampus) mutant mice that were not able to produce 11ß-HSD1 spent more time in the new arm than non-mutant mice. These mutant mice had lower levels of stress hormones in their brains and, according to the researchers’ theory, would therefore have better memories.

Aged mice that were given a placebo could not distinguish between the new arm and the other arms in the Y-maze. Mice that were treated with the UE1961 drug for 10 days spent more time in the new arm compared to the other arms.

How did the researchers interpret the results?

The researchers conclude that mice that were not able to produce 11ß-HSD1 (the mutant mice) were resistant to spatial memory deficits associated with ageing. Giving aged, normal mice the drug UE1961 – an inhibitor of 11ß-HSD1 – improved their spatial memory.

The findings suggest an avenue for further research into the use of this inhibitor in improving spatial memory. They say, however, that it also raises important safety concerns, including the fact that it is unclear how the drug affects the memory of emotionally arousing experiences (in which 11ß-HSD1 plays a part).

Conclusion

The findings from this study have been over-interpreted by the news. It is misleading to suggest that the researchers have found ‘a new drug that can slow the onset of dementia’. There are several reasons why this extrapolation is premature and not supported by this early study:

• The new drug was given to mice; nine of them.
• Dementia is a complex syndrome and there are different types (Alzheimer’s disease, vascular dementia, dementia with Lewy bodies). It can have wide-ranging effects on cognition, including memory, speech, judgement and language. It is a lot more serious and complex than ‘forgetting where the car keys are’, or forgetting names. This study did not assess the effects of the drug on other aspects of cognition outside of spatial memory.
• The longer-term effects of this drug on the physical health of the mice was not investigated, nor were the potential negative effects on other aspects of memory, particularly on how ‘emotionally arousing experiences’ are remembered in which the stress hormones are known to play a role.

Animal research is an important stage in the development of new drugs. It precedes further in-depth testing and is a preliminary step in establishing the efficacy and safety of potential new treatments.

But for many of these studies, it is unhelpful to make grand claims based on their early findings, as many potential drugs never make it further in their testing. This study is the first step, and while it may possibly lead to the development of a treatment for certain types of memory problems, this is some way in the future.