An Exciting New Avenue For Epilepsy Treatment Development

A ketogenic diet, high in fat and low in carbohydrate, has been used in the treatment of drug-resistant (refractory) childhood epilepsy since the 1920s. It forces the body to burn fats instead of carbohydrates, and this leads to a build-up of molecules called ketone bodies in the blood, which are thought to be responsible for the diet’s anti-convulsant effect in some people.

The ketogenic diet does, however, have a number of unpleasant side-effects, such as constipation, bone fracture and delayed growth; and it is generally not well tolerated by adults (who find it difficult to persevere with). Research efforts are therefore ongoing to gain a better understanding of the anti-convulsant mechanisms of the diet, so that a drug that has its benefits but avoids its side-effects can be developed to replace it. Such a treatment might also be a viable option for adults with refractory epilepsy.

Clinical studies have now shown that there is, in fact, no link between blood ketone body levels and seizure control; and this suggests that other factors must be at the root of the diet’s anti-convulsant effect. Researchers at Royal Holloway University London (RHUL) have recently made exciting progress in identifying these.

In their latest study, the team focused on molecules known as medium chain fatty acids (MCFAs), which also accumulate in the blood during the the ketogenic diet. Fatty acids are the building blocks of fats, and there are many different types depending on their structure. The reason the scientists were interested in MCFAs is because valproate (a widely prescribed anti-epileptic drug) is also a type of fatty acid; although it is a short-chain fatty acid, not a medium chain one.

Valproate has a number of unpleasant side-effects, and it poses considerable risks to the development of unborn babies if their mothers take it during pregnancy (this is referred to as teratogenicity). MCFAs are significantly different to short-chain fatty acids in terms of their size and structure, and the scientists hoped that they would find at least one that could stop seizures as effectively as valproate (if not more) AND have fewer side-effects.

The group began by identifying three MCFAs: two that are known to accumulate in the ketogenic diet (ethanoic acid and decanoic acid), and one that is also found naturally but does not tend to increase during the diet (nonanoic acid). They tested each one (at a range of doses) using cell cultures to find out i) their ability to stop seizure activity ii) whether they were toxic to liver cells and iii) their teratogenic risk, and then compared them to valproate.

The results of the first assessment showed that decanoic acid and nonanoic acid were superior to valproate in stopping experimental seizures (they required a lower dose to achieve the same effect); but this was not the case with ethanoic acid. When an ethanoic acid derivative called 4-methylethanoic acid was tested, however, it too out-performed valproate. This compound was therefore included in subsequent assessments.

Liver toxicity is notoriously difficult to assess in cell cultures, and whilst none of the molecules showed significantly greater toxicity compared to valproate, it was not easy to determine from the results whether any were less toxic.

In terms of teratogenicity, both nonanoic acid and 4-methylethanoic showed minimal risk (at all doses tested); however decanoic acid appeared to be as teratogenic as valproate at some clinical doses.

After considering these findings and weighing the benefits of each MCFA against their potential side-effects; the researchers decided to take 4-methylethanoic acid and nonanoic acid forward for further testing, in animals. Here, they assessed the tendency of each to cause drowsiness/sedation (which can be extremely debilitating to daily life) and their ability to protect neurons from damage caused by status epilepticus (SE), and again they compared them to valproate. Interestingly they found that nonanoic acid caused less sedation than valproate in the animals, but that with 4-methylethaonic acid, sedation was more pronounced. Furthermore, neither 4-methylethanoic acid nor valproate protected the brain from neuronal damage during SE, whereas in animals treated with nonanoic acid, this damage was markedly reduced.

These results are very promising, because they pinpoint nonanoic acid as a molecule that is superior to valproate in terms of seizure control and side-effects, and suggest that it might also offer protection to neurons during seizures. In time, drugs that mimic nonanoic acid’s function could potentially replace the ketogenic diet and become a viable treatment for both adults and children. They may even prove to be safer and more effective than some existing anti-epileptic drugs in certain types of epilepsy.

πηγή http://www.epilepsyresearch.org.uk/an-exciting-new-avenue-for-epilepsy-treatment-development/