Approximately one third of people with epilepsy do not respond to anti-epileptic drugs (AEDs) and continue to experience seizures. For some, alternative/additional therapies (such as epilepsy surgery, vagal nerve stimulation or a ketogenic diet) may be successful, but for others, these options are either unsuitable or ineffective. There is an urgent need for new types of epilepsy drug that act in different ways to existing AEDs, because these might be able to control seizures where current drugs have failed.

Galanin is a peptide (a fragment of a protein) that is produced in the brain and regulates a range of functions including pain, memory and mood. It has also been shown to be a potent anti-convulsant. Studies of its anti-convulsant role suggest that, during seizures, the brain increases its production of galanin, possibly as a way to protect itself against the seizure activity. Animals bred to lack galanin have also been shown to be more susceptible than normal to developing seizures.

In light of galanin's seizure-reducing effects, several groups of researchers have been developing drugs that prevent seizures by targeting the galanin system.

The first compounds produced were synthetic molecules called galanin agonists, which mimicked the functions of galanin. These were successful anti-convulsants when given to seizure-prone animal models, but their mode of action was very general and so they caused a range of unwanted side-effects.

Scientists at Scripps Research Institute, in California, have now designed a compound that targets the galanin system but, unlike the previous agonists, is more selective in its action. The compound, currently known as CYM2503, binds to one of the three receptors for galanin on nerve cells, the galanin type 2 receptor (GalR2). When administered on its own, CYM2503 has no effect on GalR2, but when galanin also binds to the receptor, CYM2503 boosts galanin's function.

The team recently tested the effects of CYM2503 on animal models that had been given a chemical to induce seizures. They compared the effects with a second (control) group that were seizure-induced but received no treatment with CYM2503. The researchers noticed that the subjects that received CYM2503 took longer to develop seizures and, when they did, the seizures lasted for a shorter time than those seen in the controls. More importantly, when the researchers examined the subjects after 24 hours, those that had been treated with CYM2503 had a much higher survival rate than those that had not.

The mode of action (MOA) employed by CMY2503 (i.e. the modification of a receptor's function) is not new; in fact it is common to several successful drugs already used to treat epilepsy, hyperparathyroidism, and AIDS. However, this is the first prospective drug that targets the galanin system using this MOA. As CMY2503 only works when galanin (a natural molecule) is present, the scientists predict that it will have fewer side effects than drugs that work alone.

These results are exciting, because they provide the first evidence that modulating the GalR2 receptor is an effective strategy for treating seizures. Drugs that target this mechanism will hopefully prove successful in treating epilepsy in the future.

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