New Resin Acid Molecules Show Promising Properties as Potential Epilepsy Drugs

New molecules, developed by researchers at Linköping University, have promising properties as possible drugs against epilepsy. A study published in the journal Epilepsy shows that several of the molecules have anti-epileptic effects.

In people with epilepsy, nerve cells in the brain become overactive, causing seizures.

Over 60 million people worldwide suffer from epilepsy. A third of them still have seizures despite taking medication, so there is a pressing need for new types of medication. “

Nina Ottosson, Senior Research Engineer, Department of Biomedical and Clinical Sciences, Linköping University

Nerve impulses are electrical signals that travel along nerves at lightning speed. Epilepsy and many other conditions occur when nerves transmit signals far too easily, at times when they should be electrically silent. Nerve impulses are created when small channels, called ion channels, located in the membranes of nerve cells pass electrically charged ions. When enough ions have entered a cell, an electrical impulse occurs, which is transmitted along a long nerve fiber and then stimulates other nerve cells. Ion channels thus play a key role in epilepsy. Many drugs currently used to prevent seizures work by affecting ion channels.

Previous work by the Linköping University research group has shown that resin acids, which are found in the resin of pine and spruce trees, can affect certain types of ion channels. Scientists used these natural resin acids as a starting point to develop new, similar molecules. The long-term goal is to create drugs that prevent epileptic seizures.

In the recently published study, researchers looked at an ion channel that affects how easily a nerve impulse is stimulated. This channel, the potassium ion channel noted hKV7.2 / 7.3, plays an important role in epilepsy. If it is closed, an epileptic seizure can occur, while the seizure can be stopped if the duct opens. A drug, retigabine, can open hKV7.2 / 7.3, which has been helpful in the treatment of severe epilepsy. Retigabine, however, affects other ion channels, particularly smooth muscle channels found, for example, in the bladder and blood vessels. This gave side effects, such as abnormally low blood pressure and difficulty urinating. Retigabine was withdrawn a few years ago.

The researchers showed in the study that several of the new resin acid molecules can open hKV7.2 / 7.3. They also investigated whether the molecules affect a tightly bound ion channel, hKV7.4, which is opened by retigabine and contributes to its side effects. Experiments with tissue from rats have shown that the new molecules have less of an effect on smooth muscles, and are therefore less likely to have adverse effects on blood vessels and the bladder. The new resin acids influence ion channels using a different mechanism than that used by retigabine. The researchers believe that the difference in the mechanism of action is significant for the effects in different tissues.

“I think the mechanism by which our molecules act on ion channels can be extremely important. We hope that through future collaborations, we will be able to bring our molecules along the path leading to a drug in clinical use, ”says Nina Ottosson.

Another important question is whether the new molecules can prevent seizures in an entire organism. The researchers thus studied the effect of molecules in zebrafish larvae in which epileptic seizures were provoked using a special substance.

“Several of the molecules had an anti-epileptic effect in these experiments when used at the same concentration as retigabine,” explains Nina Ottosson.

Scientists now continue to work for a detailed understanding of how resin acid molecules affect ion channels and how they can be improved so that they can be used as drugs.

“Patients and their loved ones contact me often, and their stories show how urgent the need for effective treatments is. It would be amazing if some of those affected could be helped in the long term by our research. But at the same time, we must realize how incredibly difficult it is to bring a molecule along the path to a new drug. Our findings may also contribute to development by spurring further research, “says Fredrik Elinder, professor in the Department of Biomedical Sciences and clinics at Linköping University.

The research was carried out in collaboration with Sophion Biosciences A / S in Denmark and researchers from the University of Copenhagen. The experiments on zebrafish were carried out in collaboration with Bioreperia AB. Funding for the research has been secured from, among others, the Swedish Research Council, the Swedish Heart and Lung Foundation, the Swedish Brain Foundation, Novo Nordisk Fonden and Parkinsonstiftelsen. Some of the researchers have applied for a patent for the resin acid molecules described in the study.