LA JOLLA, Calif.—Seeking to develop a new class of anti-seizure drugs for the estimated 50 million people worldwide who are affected by epilepsy, scientists at the Scripps Research Institute have designed a chemical compound that boosts a potent anticonvulsant molecule in the brain. According to the researchers, the compound could spark a new angle for developing drugs to treat seizures—an urgent, unmet need, as up to 30 percent of epilepsy patients do not respond to current drugs.
Scripps Research Assistant Professor Xiaoying Lu notes that there are many drugs on the market that treat epilepsy by reducing the rapid and excessive firing of neurons in the cerebral cortex. These drugs do so by targeting the mechanisms by which neurons send signals to one another. But due to individual patient variability and the diverse etiology of epilepsy, about one-third of epilepsy patients do not respond to drugs that act by this mechanism, Lu says.
"Epilepsy can come from genetics, anatomical head trauma, stroke, various neurological diseases, or even for seemingly no reason at all," she says. "Seizures are more like a symptom of epilepsy, and can have many causes, so that is why people do not uniformly respond to a single therapy. There may be certain drugs that are better for people with certain types of epilepsy—you really have to consider treatment options on a case-by-case basis."
This makes the search for additional drugs that act by different mechanisms an urgent one, Lu says, and she and her colleagues at Scripps recently published a study describing their development of new compound that effectively reduced the frequency and severity of seizures in mice and rats.
The compound, dubbed CYM2503, does so by expanding on two decades of research on the molecule galanin, a peptide produced in the brain to regulate a variety of functions and found in the early 1990s to act as a potent anticonvulsant. Recent galanin system research has shown that during seizures, the brain increases production of galanin to protect itself. Although other researchers have been successful in creating galanin agonists to act as anticonvulsants in animals prone to developing seizures, these agonists also have many unwanted side effects, Lu notes.
"Even if you are able to make it, you definitely cannot give it to patients, because it doesn't pass the blood-brain barrier," she adds.
CYM2503 also targets the galanin system, but is more selective in its action. It binds to one of the three receptors for galanin on nerve cells, the galanin receptor type 2 (GalR2). On its own, CYM2503 has no effect on GalR2, but when galanin also binds to the receptor, CYM2503 boosts galanin's function.
When the Scripps scientists tested the effects of CYM2503 on mice and rats that had received a chemical causing them to have seizures, the animals took longer to get seizures and, when they did, the seizures lasted for a shorter time. Most importantly, when the researchers looked at the animals after 24 hours, the rats that had been treated with CYM2503 had a dramatically higher survival rate than those that had not.
Because CYM2503 only works when galanin is present, Lu and her colleagues predict it will have fewer side effects than drugs that work on their own. In addition, because CYM2503 has been shown to modify the GalR2 receptor, the compound could be further studied as a potential treatment for other diseases affected by the galanin system.
"GalR2 has a neuroprotective effect on anything that causes brain injury," Lu says, "so we think it could also be investigated for its antidepressant effects, and may even be important in the study of some cancer cell lines."
For now, the researchers are still in preclinical development of CYM2503 and will next study its effect on additional seizure and chronic epilepsy models.
The Scripps study, "GalR2-positive allosteric modulators exhibits anticonvulsant effects in animal models," can be seen in the July 26 early edition of Proceedings of the National Academy of Sciences (PNAS). Lu's co-authors included Edward Roberts, Fengcheng Xia, Manuel Sanchez-Alavez, Tianyu Liu, Roger Baldwin, Stephanie Wu, James Chang, Claude G. Wasterlain and Tamas Bartfaia. The study was supported by the National Institutes of Health.
Scripps Research Assistant Professor Xiaoying Lu notes that there are many drugs on the market that treat epilepsy by reducing the rapid and excessive firing of neurons in the cerebral cortex. These drugs do so by targeting the mechanisms by which neurons send signals to one another. But due to individual patient variability and the diverse etiology of epilepsy, about one-third of epilepsy patients do not respond to drugs that act by this mechanism, Lu says.
"Epilepsy can come from genetics, anatomical head trauma, stroke, various neurological diseases, or even for seemingly no reason at all," she says. "Seizures are more like a symptom of epilepsy, and can have many causes, so that is why people do not uniformly respond to a single therapy. There may be certain drugs that are better for people with certain types of epilepsy—you really have to consider treatment options on a case-by-case basis."
This makes the search for additional drugs that act by different mechanisms an urgent one, Lu says, and she and her colleagues at Scripps recently published a study describing their development of new compound that effectively reduced the frequency and severity of seizures in mice and rats.
The compound, dubbed CYM2503, does so by expanding on two decades of research on the molecule galanin, a peptide produced in the brain to regulate a variety of functions and found in the early 1990s to act as a potent anticonvulsant. Recent galanin system research has shown that during seizures, the brain increases production of galanin to protect itself. Although other researchers have been successful in creating galanin agonists to act as anticonvulsants in animals prone to developing seizures, these agonists also have many unwanted side effects, Lu notes.
"Even if you are able to make it, you definitely cannot give it to patients, because it doesn't pass the blood-brain barrier," she adds.
CYM2503 also targets the galanin system, but is more selective in its action. It binds to one of the three receptors for galanin on nerve cells, the galanin receptor type 2 (GalR2). On its own, CYM2503 has no effect on GalR2, but when galanin also binds to the receptor, CYM2503 boosts galanin's function.
When the Scripps scientists tested the effects of CYM2503 on mice and rats that had received a chemical causing them to have seizures, the animals took longer to get seizures and, when they did, the seizures lasted for a shorter time. Most importantly, when the researchers looked at the animals after 24 hours, the rats that had been treated with CYM2503 had a dramatically higher survival rate than those that had not.
Because CYM2503 only works when galanin is present, Lu and her colleagues predict it will have fewer side effects than drugs that work on their own. In addition, because CYM2503 has been shown to modify the GalR2 receptor, the compound could be further studied as a potential treatment for other diseases affected by the galanin system.
"GalR2 has a neuroprotective effect on anything that causes brain injury," Lu says, "so we think it could also be investigated for its antidepressant effects, and may even be important in the study of some cancer cell lines."
For now, the researchers are still in preclinical development of CYM2503 and will next study its effect on additional seizure and chronic epilepsy models.
The Scripps study, "GalR2-positive allosteric modulators exhibits anticonvulsant effects in animal models," can be seen in the July 26 early edition of Proceedings of the National Academy of Sciences (PNAS). Lu's co-authors included Edward Roberts, Fengcheng Xia, Manuel Sanchez-Alavez, Tianyu Liu, Roger Baldwin, Stephanie Wu, James Chang, Claude G. Wasterlain and Tamas Bartfaia. The study was supported by the National Institutes of Health.
