Is it a breakthrough in narcolepsy? Probably not!

There have been several articles published in the mainstream press recently about narcolepsy and how it can be “cured”. These stories all came from the same scientific paper from researchers at the University of Oregon which was published in The Journal of Neuroscience this month.

It is a very interesting story; scientists have found that lethargy in illness is probably caused by a specific group of inflammation-sensitive orexin neurons in the hypothalamus. If a subject has an illness accompanied by inflammation the production of orexin by these neurons is reduced making the individual feel lethargic and sleepy. The researchers feel that it may be a very old system (the hypothalamus is one of the oldest areas of the brain) which is used to divert energy into fighting the infection; something that could have been very useful when we were all living in caves.

When the researchers injected the brains of rats with orexin they were able to restore orexin signalling and get the rats moving again. From that they determined that orexin replacement is “a viable therapeutic avenue for sickness induced lethargy”. They then go on to say that "Because the role of orexin in sleep disorders like narcolepsy has been known for several years, the drug development efforts aimed at restoring orexin signalling are at an advanced state and nearly ready for clinical application." That was the bit that intrigued the newspapers of course!

Why are we less than impressed with the significance of these findings for people with narcolepsy?

Well, intrinsically nothing new can be found in the article for people with narcolepsy. It is interesting that these neurons can activate and switch off production for a while. But, the fact that for most narcoleptics, orexin reduction is the cause of their condition is old news. We have known for some time that destruction of orexin neurons causes narcolepsy, and we assume that replacement of orexin cures it.

The first point to make is that the rats used were not narcoleptic, it is not possible to take the information and use it wholesale on narcoleptics. The over-production of Trib 2s were not found in the brains of the rats and so it isn’t a like-for-like test. Also, they didn’t have damaged orexin neurones or receptors. If they had been left alone and had got over the inflammation orexin production would have returned to normal.

We believe that, if the orexin deficiency could be reversed, the symptoms of narcolepsy could similarly be reversed. The problem is orexin itself cannot be administered orally and, even if you inject it like insulin, it will not penetrate into the brain because of the ‘blood-brain barrier’. The problem is that the chemical is a very large molecule, so it doesn't get into the brain, except by direct injection into the brain at the moment. Unless scientists can develop a means of persuading orexin to pass the blood-brain-barrier, which is unlikely, the future of an orexin-based treatment will depend on the development of synthetic orexin-like drugs – ‘orexin agonists’ as they are called. To the best of our knowledge such agonists are not ‘nearly ready for clinical application’ as stated by the authors of this paper. It will several years yet before such drugs will be available for clinical use.

The good news is that the particular class of receptor to which orexin receptors belong to are very good drug targets. If you look at what your clinician recommends in terms of drugs more than half of them actually target one or more of these receptors.

If an orexin agonist could be found, another advantage would be that it would produce a physiological wakefulness as compared with dexamfetamine and other stimulants currently in use. They basically activate a wide variety of neurons in a rather nonselective way and force the brain to wake up, while an orexin receptor agonist would, we assume create a more normal physiological wakefulness.

For people with narcolepsy orexin remains the key to a more normal life. As just mentioned, the use of orexin itself seems unfeasible. A synthetic orexin agonist with an acceptable profile will ultimately be developed and will herald the future of narcolepsy treatment. A future that is still, however, some way away.