Safe Drug Recovers Memories Lost to Sleep Deprivation, Dutch Scientists Find

Highlights: 

• Roflumilast prevents memory loss triggered by sleep deprivation. 
• Roflumilast may counteract the reduction in a critical protein necessary for memory formation. 
• Human studies exploring the memory-restoring effects of roflumilast and similar drugs have not been conducted. 

The best way to remember something new is to sleep on it, as sleep strengthens memory formation. The opposite is true, as sleep deprivation following a learning experience can lead to impairments in memory formation. Now, researchers from the University of Groningen in the Netherlands have found that the prescription drug roflumilast prevents sleep deprivation-induced memory impairments in mice. 

Testing the Memories of Mice 

Mice have a natural curiosity that propels them to explore new spaces. When an object is moved to a new location, mice will explore that object with more vigor than an object known to have already been there. Thus, researchers can use the duration of time a mouse spends exploring an object to deduce whether the mouse remembers that object’s location (i.e., they spend more time exploring objects in new locations). This is the basis of the object-location memory (OLM) task, which the University of Groningen scientists employed to explore the mind of mice. 

Within a mouse-sized arena, two phases to the OLM task take place: the training session and the test session. During the training session, each mouse explores the initial location of two objects. Since both objects are new during the training session, the mouse will explore both equally. For the test session, which takes place at least one day after the training session, one of the two objects is moved. This time (if it remembers the training session) the mouse will explore the moved object more than the unmoved object. However, if during the test session, the mouse explores each object equally, it is deduced that the mouse forgot the initial location of the objects learned in the training session. 

Losing and Finding Memories

The researchers found that losing sleep seemingly equated to losing memories. They determined this by depriving mice of six hours of sleep immediately following training sessions. As a result, during the test session, the sleep-deprived mice explored both objects equally, suggesting they forgot the training session. Remarkably, however, if the sleep-deprived mice were injected with 0.03 mg/kg of roflumilast (about 100 mg for humans) preceding the test session, the mice explored the moved object more than the unmoved object, suggesting their memory was intact.

Furthermore, when the test session was held five days (versus one day) after the training session, sleep-deprived mice injected with roflumilast still explored the newly located object more than the seemingly stationary object. These findings suggest that memories lost to sleep deprivation can be recovered by roflumilast even five days after a learning experience. 

How Does Roflumilast Recover Inaccessible Memories? 

Roflumilast belongs to a class of drugs called phosphodiesterase (PDE) inhibitors. PDE is an enzyme that degrades a signaling molecule critical for forming new memories, called cAMP (cyclic adenosine monophosphate). Furthermore, sleep deprivation has been shown to reduce cAMP levels. Thus, inhibiting cAMP’s degradation with roflumilast can essentially restore cAMP levels. Indeed, other PDE inhibitors like the erectile dysfunction drug Vardenafil have been shown to restore lost memories. With this in mind, the Dutch scientists hypothesize that increasing cAMP levels activates neurons in the hippocampus, which is the area of the brain responsible for the formation of new memories. However, more research is needed to determine the validity of this hypothesis. 

Can Roflumilast Recover Human Memories? 

The research at the University of Groningen was led by Dr. Robbert Havekes, who recently presented data showing that roflumilast not only restores spatial but also social memories lost to sleep deprivation. He said, 

“This research shows that social and spatial memories seemingly lost through sleep deprivation can be recovered. Although these studies were carried out in mice, they suggest that it may be possible to recover people’s lost social and spatial memories using certain drug treatments that are already approved for human use.”

Based on animal studies, roflumilast, and other PDE inhibitors have the potential to restore lost memories in humans. However, no human studies testing this possibility have been conducted. Therefore, whether roflumilast can recover human memories is largely unknown, as it pertains to clinical trials.