A promising target to treat cognitive disorders identified

At least in the case of mice, all that needs to be done to enhance the cognitive ability is to inhibit the activity of an enzyme — phosphodiesterase-4B (PDE4B). Mice that have the enzyme inhibited learnt faster, remembered events longer and solved complex exercises better than normal mice. The results of the study were published today in the journal Neuropsychopharmacology.

The PDE4B enzyme is widely distributed throughout the brain in humans, monkeys and rodents and has prominent expression in the cerebral cortex and other areas of the brain. Changes in the expression and localisation of the enzyme in hippocampal neurons have been found to be associated with learning and memory.

Besides enhancing memory, the mutant form of PDE4B (Y358C) can also counter age-related cognitive decline, cognitive disorders such as Alzheimer’s disease and schizophrenia, and other conditions. The PDE4B is a risk gene and has been associated with a rare genetic cause of schizophrenia.

S.J. Clapcote, one of the corresponding authors from the University of Leeds, altered a gene in mice to inhibit the activity of the enzyme and investigated the neural and behavioural effects.

Compared with normal mice, the mutant mice were quick to learn the location of a hidden escape platform and showed a better ability to recognise another juvenile mouse with which it had contact a day before. The working spatial memory showed remarkable improvement in the mutant mice compared with the normal ones.

While the preference for displaced objects was the same when both mice types were given 10 minutes of acquisition, only the mutant ones showed this preference when the time of acquisition was cut by half.

The mutant ones also demonstrated greater exploratory behaviour and preference for displaced objects even when the environmental threat was increased — brighter lights and being in a transparent arena at 1 metre elevation. While the normal mice did not show any preference for displaced objects under such aversive environments following 10 minutes of acquisition, the preference for displaced objects was “maintained” in the mutant mice even when the acquisition was reduced to five minutes.

But an “increased exploratory tendency does not equate to improvement in general cognitive performance,” the authors write.

The mutant ones also displayed lower levels of anxiety in several tests. In particular, the mutant mice showed “functional impairment on 7-day fear memory.” As a result, they failed to show their natural robust innate fear response to cat urine seven days after conditioning.

“Negative influence of environmental threat on object recognition memory formation suggests dissociation between fear and memory formation,” the authors note. According to the authors, the reduction in fear memory is “unlikely to represent extinction of fear memory” but may be due to PDE4B dysfunction.

So how does the work, which has only looked into learning, memory, exploratory tendencies and fear in mice and not into cognitive disorders be useful in finding a new treatment for people with cognitive disorders?

“The current work does not specifically address cognitive disorders. What it shows is that inhibiting PDE4B have cognition-enhancing effects in otherwise healthy mice. We will now go on to investigate whether inhibiting PDE4B have cognition-enhancing effects in mice with cognitive impairment, such as aged mice or a mouse model of Alzheimer’s disease,” Dr. Clapcote said in an email to this Correspondent.

“It is already known that the non-subtype specific PDE4 inhibitor rolipram (targeting all of four subtypes A–D) has shown therapeutic benefit in laboratory rodent models of psychiatric and neurological diseases, such as stroke-induced memory deficits in rats, age-related memory deficits, and memory deficits in a transgenic mouse model of Alzheimer’s disease. The problem with rolipram, though, is that it is poorly tolerated in humans due to nausea and vomiting. A brain-penetrant PDE4B-specific inhibitor would likely overcome this limitation,” he added.

Answering if reduced anxiety will be useful, he said: “While having less anxiety might be beneficial, it might not be good to have too much risk-taking behaviour. Yes, the treatment might have the same effect in humans, which would be monitored for during clinical trials.”

“In the future, medicines targeting PDE4B may potentially improve the lives of individuals with neurocognitive disorders and life-impairing anxiety, and they may have a time-limited role after traumatic events,” Dr. Alexander McGirr, a co-author from the University of British Columbia, was quoted as saying in a University of Leeds press release.

“Cognitive impairments are currently poorly treated, so I’m excited that our work using mice has identified phosphodiesterase-4B as a promising target for potential new treatments,” Dr. Clapcote said in the release.

The researchers are now working on developing drugs that will specifically inhibit PDE4B and will eventually undertake animal studies. “If we obtain further funding, I think a brain-penetrant PDE4B-specific inhibitor could be developed and tested in mice within three years,” Dr. Clapcote said.

Published in The Hindu on August 14, 2015