“This compound really provides a new angle for developing drugs to treat seizures,” says Scripps Research Assistant Professor Xiaoying Lu, who co-authored the paper with Professor Edward Roberts, Chair of the Molecular and Integrative Neurosciences Department Tamas Bartfai, and colleagues.
As described this week in Proceedings of the National Academy of Sciences (PNAS), the new compound effectively reduced the frequency and severity of seizures in mice and rats.
About 50 million people worldwide are affected by epilepsy, a disease characterized by recurrent, unprovoked seizures. As a result of the seizures, people may have violent muscle spasms or lose consciousness and, in some cases, suffer from brain damage or die. Epileptic seizures are caused by the rapid and excessive firing of a population of neurons in an area of the brain known as the cortex. The dozen-plus medicines currently on the market to treat epilepsy work to reduce this excessive firing primarily by targeting the mechanisms by which neurons send signals to one another.
However, as many as 30 percent of people with epilepsy do not respond to current drugs, making the search for additional drugs that act by different mechanisms an urgent one.
A promising new approach to treating seizures is to target a molecule called galanin. Galanin is a peptide, a fragment of a protein, produced in the brain to regulate a variety of functions, such as pain, memory, addition, mood, and appetite. In the late 1990s, researchers discovered that galanin is also a potent anticonvulsant.
Recent research suggests that when seizures occur the brain steps up production of galanin, possibly as a way to protect itself against the seizures. As a result, mice engineered to lack galanin are more susceptible to developing seizures.
Because galanin seems to play a role in reducing seizures, several groups of researchers, including those at Scripps Research, have been working to develop drugs that target the galanin system.
The first category of such compounds consists of synthetic molecules that mimic galanin’s functions (called agonists) and include Galnon, developed by Bartfai’s group. Galnon and other galanin agonists have been shown to act as anticonvulsants when given to animals that were rendered prone to developing seizures. But these agonists have several drawbacks as potential therapeutic agents. For one thing, because Galnon acts relatively broadly, it may have unwanted side effects.
A New Mechanism
Lu, Roberts, Bartfai, and colleagues at Scripps Research have now designed a compound that targets the galanin system but, unlike the previous agonists, is more selective in its action. The compound, dubbed CYM2503, 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.
The researchers tested the effects of CYM2503 on mice and rats that had received a chemical causing them to have seizures. The animals that received CYM2503 took longer to get the 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.
This mechanism of action, modifying a receptor’s function, is common to many successful drugs that have been developed for the treatment of a number of conditions, including epilepsy, hyperparathyroidism, and AIDS, but not yet for drug candidates targeting galanin system.
“It is a double breakthrough,” says Bartfai. “The compound is a first new mode-of-action anticonvulsant and it represents a new mechanism of molecular action.”
Because CYM2503 only works when galanin, a natural molecule, is also present, the researchers predict it will have fewer side effects than drugs that work on their own. This study provides the first evidence that modulating the GalR2 receptor is an effective strategy for treating seizures, thus opening the door for the development of drugs that target this mechanism.
“Based on the known functions of the GalR2 receptors, it may also work in treating depression and in protecting the brain from damage,” says Lu.
Roberts adds, “This is an area we can now move into. We plan to go systematically through other conditions.”
In addition to Lu, Roberts, and Bartfai, co-authors of the article “GalR2-positive allosteric modulators exhibits anticonvulsant effects in animal models” include Fengcheng Xia, Manuel Sanchez-Alvarez, Tianyu Liu, Stephanie Wu, and James Chang of Scripps Research, and Roger Baldwin and Claude G. Wasterlain of Veterans Affairs Greater Los Angeles Health Care System and the David Geffen School of Medicine at University of California, Los Angeles. For more information on the paper, see http://www.pnas.org/content/early/2010/07/15/1008986107.abstract
This study was supported by the National Institutes of Health.
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The Scripps Research Institute is one of the world’s largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Scripps Florida is located in Jupiter, Florida. See www.scripps.edu
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