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Body clock drugs could ease psychiatric disorders

Researchers have used a drug to reset and restart the 24 hour body clock of mice, which could eventually help with human difficulties including some psychiatric disorders, jet lag and the health impacts of shift work.

The work was led by Professor Andrew Loudon from the University of Manchester and Dr Mick Hastings of the MRC Laboratory of Molecular Biology in Cambridge, working with a team of scientists from Pfizer led by Dr Travis Wager.

Professor Loudon commented: ‘It can be really devastating to our brains and bodies when something happens to disrupt the natural rhythm of our body clocks. This can be as a result of disease or as a consequence of jet lag or frequent changing between day and night shifts at work.

‘We've discovered that we can control one of the key molecules involved in setting the speed at which the clock ticks and in doing so we can actually kick it into a new rhythm.’

The circadian clock is a complex system of molecules in every cell that drives the rhythmicity of everything from sleep in mammals to flowering in plants. Light and the day–night cycle are important for resetting the clock, and fine adjustments are made through the action of several enzymes – including casein kinase 1, which has been the centre of this project.

Professor Loudon continued: ‘The circadian clock is linked to the 24 hour day–night cycle and the major part of the clock mechanism “ticks” once per day. If you imagine each “tick” as represented by the rise and fall of a wave over a 24 hour period, as you go up there is an increase in the amount of proteins in the cell that are part of the clock mechanism, and as you go down, these substances are degraded and reduce again. What casein kinase 1 does is to facilitate the degradation part.

‘So you can imagine that the faster casein kinase 1 works, the steeper the downward part of the wave and the faster the clock ticks – any change in casein kinase 1 activity, faster or slower, would adjust the “ticking” from 24 hours to some other time period.’

The team found a drug that slows casein kinase 1 down and used it in mice in which the circadian rhythm had ceased. In live mice and in cells and tissue samples from mice, they were able to re-establish the ticking of the clock by using the drug to inhibit the activity of casein kinase 1.

Professor Loudon concluded: ‘We've shown that it's possible to use drugs to synchronize the body clock of a mouse and so it may also be possible to use similar drugs to treat a whole range of health problems associated with disruptions of circadian rhythms. This might include some psychiatric diseases and certain circadian sleep disorders. It could also help people cope with jet lag and the impact of shift work.’

Further reading

Meng et al. (2010) Entrainment of disrupted circadian behavior through inhibition of casein kinase 1 (CK1) enzymes. PNAS 107, 15240

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Biotherapeutics  •  Target Identification/ Validation


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