Compounds in resin act on an ion channel that is important for epileptic seizures. Researchers have identified the most promising candidates for developing new medication for people with epilepsy.
Good news may be on the way for the one third of the people with pharmacoresistant epilepsy: that is, when medicine does not control seizures.
Researchers in Sweden and Denmark have identified some very promising drug candidates based on resin acid derivatives.
They tested their effectiveness and found that that the drugs not only act on a cellular ion channel that is important for epilepsy but also appear to have almost none of the side-effects of the existing antiseizure drugs.
“About 65 million people worldwide have epilepsy, and one third have pharmacoresistant epilepsy. New types of drugs are therefore urgently needed, and I hope and believe that in the future we can develop our molecules into new treatments,” explains a researcher behind the study, Nina Ottosson, Principal Research Engineer, Linköping University, Sweden.
The research has been published in Epilepsia.
Drugs must target the right ion channels
Epileptic seizures result from the neurons in the brain sending too many signals to neighbouring cells, even when this is not necessary, and they should be at rest.
These signals occur when small channels in the neurons allow electrically charged ions to pass through the channels. When enough ions have entered the neuron, it fires an electrical signal towards the neighbouring cell, which retransmits the signal further into the system and stimulates even more neurons. A seizure results when enough neurons are stimulated.
Because the ion channels play such a major role in developing seizures, many epilepsy drugs also target the ion channels.
One such drug is retigabine, which was marketed years ago but subsequently withdrawn.
Retigabine exerts its antiseizure effect by opening the hKV7.2/7.3 ion channel, which has an important role in epilepsy. When it is closed or does not function because of mutations, people may get epileptic seizures, but opening this channel can prevent them.
However, this promising drug fell short because it also affected the smooth muscle fibres in the blood vessels and bladder. This led to low blood pressure and difficulty urinating. Retigabine was therefore withdrawn.
“Retigabine works really well against seizures. However, because the drug activated both the hKV7.2/7.3 ion channel and the hKV7.4 ion channel, it produced many side-effects. A drug that can activate hKV7.2/7.3 without binding to hKV7.4 therefore has great potential,” says Nina Ottosson.
New molecules only affect the appropriate channels
The researchers tested several derivatives of naturally occurring resin acids.
Previous findings from the research group that includes Nina Ottosson has shown that certain compounds in resin from pine and spruce trees can activate various ion channels in cells. The researchers used these resin acids to develop numerous molecules with similar effects.
In experiments with rat tissue, the researchers examined how their newly developed molecules affected hKV7.4. The molecules, like retigabine, opened the hKV7.2/7.3 channel but had little effect on hKV7.4 and the smooth muscle fibres.
Nina Ottosson explains that the researchers’ molecules use a different mechanism to interact with the hKV7.2/7.3 channel that does not affect hKV7.4 as strongly as retigabine.
Nina Ottosson also says that they found that clinically relevant concentrations also do not appear to affect the ion channels in the heart.
“This suggests that our drugs may be effective against seizures without having too many side-effects on blood pressure and the bladder,” explains Nina Ottosson.
Prevented seizures in zebrafish
To validate the promising results, the researchers also tested their molecules on zebrafish larvae to determine whether they could inhibit seizures in a live animal.
Exposing zebrafish larvae to various chemicals can provoke epileptic seizures, but the experiments showed that the new molecules prevented the zebrafish larvae from having seizures.
“This shows that our molecules influence the development of seizures when used in the same quantities as in retigabine. The research also showed that our molecules cross the blood–brain barrier of the zebrafish larvae and thus affect the part of the brain where the epileptic seizures originate. The experiments also showed no indications that the molecules are toxic or produce new types of side-effects,” says Nina Ottosson.
Inspired by the promising results, the researchers are now planning further studies of their molecules in larger animals initially and hopefully also in clinical trials with people later.
