Drug Discovery Opinion

Lack of sleep has been said to have a similar effect on concentration and performance as being drunk and can lead to higher levels of stress, anxiety, and depression and also to unnecessary risk-taking. Although sleep deprivation is known to impair performance and have negative effects on learning and memory, the molecular mechanisms underlying changes in brain function remain poorly understood.

Researchers at the University of Pennsylvania, the University of Glasgow and the University of Toronto have now shown that brief sleep deprivation in mice leads to increased levels of PDE4 and reduced levels of cAMP in the hippocampus, an area of the brain associated with learning and memory. When the mice were treated with the PDE4 inhibitor, rolipram, cAMP signalling was restored, together with synaptic plasticity and hippocampus-dependent memory. The team hope that their findings, which are published in the journal Nature, will lead to new treatments for the cognitive impairment that accompanies sleep disturbances seen in disorders such as sleep apnea, Alzheimer’s disease and schizophrenia.

PDE4 is the major cAMP-metabolising enzyme in inflammatory and immune cells and inhibitors were originally investigated for the treatment of asthma, rhinitis and COPD. Dose-limiting nausea and vomiting have been observed with PDE4 inhibitors, likely because of lack of selectivity for the different isoforms of PDE4, and these side effects will need to be overcome if PDE4 inhibitors are to be used to reduce the impact of sleep deprivation.

The study represents an important advance in understanding how lack of sleep affects our brain and, although many of us may just prefer a decent night’s sleep, could lead to much needed help when lifestyle or illness make this an impossible dream.

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