Category: Epilepsy

New research from Rhode Island Hospital found that reduced levels of brain-derived neurotrophic factor (BDNF), a protein in the brain that encourages growth of neurons, may be a trait marker for individuals with psychogenic non-epileptic seizures (PNES) (seizures that are psychological in origin). The findings are published in the October 4, 2010, issue of Neurology, the medical journal of the American Academy of Neurology.

Past studies have shown decreased levels of BDNF in the serum of patients with psychiatric disorders such as major depressive disorder and conversion disorders (a condition in which a patient displays neurological symptoms such as numbness or seizures when no neurological lesion or pathology is found). Children with epilepsy have been found to have increased levels of BDNF compared to healthy controls. Serum BDNF levels, however, have not been investigated in adult patients with epileptic seizures (ES). With this in mind, researchers from Rhode Island Hospital hypothesized that BDNF would differentiate between ES and PNES.

W. Curt LaFrance, Jr., MD, MPH, director of neuropsychiatry and behavioral neurology at Rhode Island Hospital, and assistant professor of psychiatry and neurology (research) at The Alpert Medical School of Brown University led the study of three groups of patients — one group with confirmed PNES, one group with ES and one healthy control group. The patients were also screened for comorbid depression as well, as past studies have suggested that chronic antidepressant use increases serum BDNF in patients with depression. More than half (8 of 13) of the patients in the PNES group were diagnosed with mild depression and were taking psychotropic (antidepressant) medication.

LaFrance and his fellow colleagues from Brown University found decreased levels of serum BDNF in both the PNES and ES groups when compared to the healthy control group. They believe these findings are significant in that it would be expected that the PNES patients taking antidepressant medications would have an increased level of serum BDNF. There were no significant differences in the levels of serum BDNF among all the patients in the PNES group, whether they were taking antidepressants or not. As a result, they believe that the reduced levels of BDNF may be a biomarker for PNES.

LaFrance says, "While BDNF may play a similar role in the pathophysiology of depression and PNES, the differential response of serum BDNF to antidepressants in patients with psychogenic nonepileptic seizures could highlight an important difference. The fact that antidepressants did not increase serum BDNF levels in our study and that there were no BDNF differences between patients with PNES who were depressed and those who did not have depression would suggest that serum BDNF might represent a trait marker of PNES. This could potentially be useful in understanding the pathophysiology of conversion disorders."

The study also found decreased levels of BDNF in adult patients with epileptic seizures, unlike the elevated levels found in children with ES. LaFrance comments, "This result is unexpected given the findings of elevated serum BDNF levels in children and the studies investigating BDNF concentrations in adult patients with ES."

LaFrance noted, "A model that may provide a unifying hypothesis on the decreased serum BDNF findings in both seizure groups may not be related to seizures — it may be related to stress. Stress has been shown to lower BDNF, and a shared characteristic of patients with epilepsy or with nonepileptic seizures is fear of the next seizure. There may be great potential for biomarkers for PNES and for treatment response." Based on these findings, LaFrance and his colleagues propose that additional studies of BDNF levels take place to provide further insight into the role of BDNF in seizure disorders.

The study was funded by grants from Brown University and the Matthew Siravo Memorial Foundation. Other researchers involved in the study with LaFrance include, Edward Stopa, MD, and Andrew Blum, MD, PhD, of Rhode Island Hospital and The Alpert Medical School, and Katherine Leaver, BS, and George D. Papandonatos, PhD, of Brown University.

Researchers from the Arkansas Epilepsy Program found treatment with rufinamide results in a significant reduction in seizure frequency compared with placebo, for patients with uncontrolled partial-onset seizures (POS). Details of this study are now available online in Epilepsia, a journal published by Wiley-Blackwell on behalf of the International League Against Epilepsy.

Epilepsy affects up to 2% of the worldwide population according to the Centers for Disease Control and Prevention. More than half of these patients experience POS, or focal seizures, which are initiated in one part of the brain. Despite an expanding number of antiepileptic drugs (AEDs) available to treat partial-onset epilepsy, about one-third of epilepsy patients remain resistant to available treatments and many more experience intolerable side effects, driving the search for therapeutic alternatives. The current study evaluated rufinamide, an AED with a novel triazole-derivative structure, to confirm its efficacy and safety at a dose of 1,600 mg twice daily as adjunctive treatment for refractory POS.

Eligible patients were male or female, aged 12-80 years, with POS with or without secondarily generalized seizures. Patients' seizures were inadequately controlled on stable doses of up to three concomitantly administered AEDs, with no evidence of AED treatment noncompliance. All medication taken regularly by patients, including AEDs, remained unchanged for at least 1 month prior to study start and throughout the study. Patients were enrolled at 61 centers in the U.S. and at four centers in Canada between February 2006 and March 2009. In total, 357 patients were randomly assigned to receive rufinamide (n = 176) or placebo (n = 181) and entered the titration phase, and 139 and 156 patients, respectively, completed the study. This study comprised a 56-day baseline phase (BP), 12-day titration phase, and 84-day maintenance phase (MP).

The researchers found that treatment with rufinamide resulted in a statistically significant reduction in total partial seizure frequency compared with placebo. Results also showed a 50% reduction in responder rate and total partial seizure frequency rate in patients treated with rufinamide. Several exploratory efficacy variables, including at least 75% responder rate and increase in the number of seizure-free days, were also associated with notably better results for rufinamide.

With respect to efficacy by seizure type, rufinamide was significantly superior to placebo for complex partial seizures, the most common seizure type, and numerically superior to placebo for simple partial seizures and secondarily generalized partial seizures. The median reduction in secondarily generalized partial seizures of 40% in this study is consistent with that previously observed at identical rufinamide dosage.

Study leader Victor Biton, M.D., comments, "Overall, there were no significant pharmacokinetic (PK) effects on either rufinamide or any second-generation AED when given with other medications." The research team confirmed PK results found in previous studies — showing lower oral bioavailability of rufinamide at higher doses, increased clearance of rufinamide with increasing body weight, and no effect of prolonged rufinamide dosing on the PK of rufinamide."

"Our study demonstrates that rufinamide is effective as adjunctive therapy in reducing total partial seizure frequency in treatment-refractory adolescent and adult patients, and confirms the known safety and tolerability profile of rufinamide in this patient population," concludes Dr. Biton.

---

Journal Reference:

1. Victor Biton, Gregory Krauss, Blanca Vasquez-Santana, Francesco Bibbiani, Allison Mann, Carlos Perdomo, and Milind Narurkar. A Randomized, Double-blind, Placebo-controlled, Parallel-group Study of Rufinamide as Adjunctive Therapy for Refractory Partial-onset Seizures. Epilepsia, October 1, 2010 DOI: 10.1111/j.1528-1167.2009.02729.x

A type of neuron that, when malfunctioning, has been tied to epilepsy, autism and schizophrenia is much more complex than previously thought, researchers at MIT's Picower Institute for Learning and Memory report in the Sept. 9 issue of Neuron.

The majority of brain cells are called excitatory because they ramp up the action of target cells. In contrast, inhibitory cells called interneurons put the brakes on unbridled activity to maintain order and control. Epileptic seizures, as well as symptoms of autism and schizophrenia, have been tied to dysfunctional inhibitory cells.

"Too much activity and you run the risk of uncontrolled activity, while too little leads to cognitive and behavioral deficits," said Mriganka Sur, Paul E. Newton Professor of Neuroscience, whose laboratory carried out the study. "Normal brain development and function hinges on the delicate balance between excitation and inhibition."

For a long time, interneurons, which make up only one-fifth of brain cells, were thought to be a kind of generic, homogenous shutdown agent. The MIT study points to a new view: At least some interneurons have very precise responses and form specific connections and circuits.

"If these cells are targeted in brain disorders, then these disorders must arise from precise dysfunction in specific circuits," said Sur, head of the MIT Department of Brain and Cognitive Sciences. "This study sheds light on precisely what is going on in these circuits that may be targeted for future treatments."

Inhibitory cells are diverse: researchers are only starting to discern distinct electrophysiological profiles, shapes and molecular signatures among the 20 or more known types.

But all interneurons fall into two clear subtypes: those that target the cell body, or soma, of their target cells and those that target the branchlike dendrites. The soma-targeting type expresses a protein called parvalbumin and has been linked to brain disorders and circuit development. This type of interneuron was thought to dampen activity uniformly across the cortex. "Our paper overturns this view," Sur said.

"These neurons had been thought to have only broad response features that would nonspecifically dampen their target cells. Our finding indicates that they have well-defined properties and functions," he said.

MIT graduate student Caroline Runyan and postdoctoral fellows James Schummers, Audra Van Wart and Nathan Wilson used cutting-edge techniques to examine the properties of parvalbumin-expressing inhibitory neurons.

With the help of mice genetically engineered to have just these cells fluoresce red in their visual cortex, the researchers used a sophisticated technique called two-photon imaging to identify and record the activity of these cells in living animals.

They found that parvalbumin-expressing interneurons have a range of response features. Many of these cells have precisely tuned responses. Some only respond to very specific signals and locations in space.

"These cells are components of and contributors to highly specific networks that shape the selectivity of neuronal responses," Runyan said. "They need to be defined by a combination of features, including structure, connections, gene expression profiles, electrophysiological properties and response types.

"This study supports the idea that individual cell classes may provide specific forms of inhibition and serve unique functions," she said.

---

Journal Reference:

1. Caroline A. Runyan, James Schummers, Audra Van Wart, Sandra J. Kuhlman, Nathan R. Wilson, Z. Josh Huang, Mriganka Sur. Response Features of Parvalbumin-Expressing Interneurons Suggest Precise Roles for Subtypes of Inhibition in Visual Cortex. Neuron, 2010; 67 (5): 847-857 DOI: 10.1016/j.neuron.2010.08.006

Major depression is a common and disabling brain condition marked not only by the presence of depressed mood but also by its effects on sleep, energy, decision-making, memory and thoughts of death or of suicide.

Major depression affects 15 million adults in the U.S., and the World Health Organization projects that by 2020, it will be the largest contributor to disability in the world after heart disease.

While antidepressants have helped many to recover and resume their lives, only 30 percent of patients will experience full remission with the first medication they use. Patients typically move on to try a series of other antidepressants. A persistent problem with such drugs has been major side effects, including obesity, sexual dysfunction, fatigue, drowsiness and nausea.

Now, a unique new therapy that applies electrical stimulation to a major nerve emanating from the brain is showing promise.

In a recently completed clinical trial at UCLA, trigeminal nerve stimulation (TNS) achieved an average of a 70 percent reduction in symptom severity over an eight-week study period. The study's principal investigator, Dr. Ian A. Cook, the Miller Family Professor of Psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA, presented the results at a recent National Institutes of Health conference on depression and other psychiatric disorders, noting that 80 percent of the subjects achieved remission, a highly significant result in this pilot study.

TNS is not new to UCLA. It was pioneered for treatment-resistant epilepsy in humans by Dr. Christopher M. DeGiorgio, a UCLA professor of neurology. The results of a positive 12-patient feasibility trial in epilepsy were reported last year in the journal Neurology. A larger, double-blind pilot epilepsy clinical trial is underway at UCLA and the University of Southern California.

The stimulator that was used in the depression clinical trial is about the size of a large cell phone. Two wires from the stimulator are passed under the clothing and connected to electrodes attached to the forehead by adhesive. The electrodes transmit an electrical current to the nerve. All the patients in the trial used the device for approximately eight hours every night while asleep. In contrast to antidepressants, no major side effects were noted.

"The major branches of the trigeminal nerve in the face are located close to the surface of the skull and can be stimulated either with non-invasive external electrodes, as we used in this trial, or with minimally invasive subcutaneous electrodes," Cook said.

He added that some patients may prefer to have miniature subcutaneous electrodes implanted under the skin rather than applying new electrodes daily.

In describing TNS, DeGiorgio, co-principal investigator for the depression trial, explained that what is remarkable about the TNS approach is that it is possible to send signals to key structures deep in the brain without penetrating into the skull.

Cook hypothesized that electrical stimulation of the trigeminal nerve generates a cascading sequence of events in the existing neuronal infrastructure. In essence, he said, "TNS provides a high-bandwidth pathway into the brain."

To help bring the TNS out of the laboratory and into patient care, UCLA's Office of Intellectual Property recently executed an exclusive worldwide license for the TNS with NeuroSigma, a Los Angeles-based neuromodulation company formed in 2008 to commercialize promising technologies developed at leading universities and research institutions. DeGiorgio and Cook are among UCLA's inventors of the TNS technology and are unpaid advisers to NeuroSigma. Dr. Antonio De Salles and Jack Judy, also UCLA faculty members, are co-founders of NeuroSigma and are minority shareholders. They report no role in this project.

The project was supported by the Joanne and George Miller and Family Endowment in Depression Research and by an anonymous philanthropic donation to UCLA.

Production of new nerve cells in the human brain is linked to learning and memory, according to a new study from the University of Florida. The research is the first to show such a link in humans. The findings, published online and in an upcoming print issue of the journal Brain, provide clues about processes involved in age- and health-related memory loss and reveal potential cellular targets for drug therapy.

The researchers studied how stem cells in a memory-related region of the brain, called the hippocampus, proliferate and change into different types of nerve cells. Scientists have been unsure of the significance of that process in humans.

"The findings suggest that if we can increase the regeneration of nerve cells in the hippocampus we can alleviate or prevent memory loss in humans," said Florian Siebzehnrubl, Ph.D., a postdoctoral researcher in neuroscience in the UF College of Medicine, and co-first author of the study. "This process gives us what pharmacologists call a 'druggable target.'"

Over the past two decades, several studies have shown that new nerve cells are generated in the hippocampus. In animal studies, disrupting nerve cell generation resulted in the loss of memory function, while increasing the production of new nerve cells led to improved memory.

To investigate whether the same is true in humans, the UF researchers, in collaboration with colleagues in Germany, studied 23 patients who had epilepsy and varying degrees of associated memory loss. They analyzed stem cells from brain tissue removed during epilepsy surgery, and evaluated the patients' pre-surgery memory function.

In patients with low memory test scores, stem cells could not generate new nerve cells in laboratory cultures, but in patients with normal memory scores, stem cells were able to proliferate. That showed, for the first time, a clear correlation between patient's memory and the ability of their stem cells to generate new nerve cells.

"It is interesting and provocative, but we need to do more work because it's not clear what comes first — the severe epilepsy or the change in the stem cells," said Jack Parent, M.D., an associate professor of neurology and co-director of the EEG/Epilepsy Program at the University of Michigan, who was not involved in the study. "It was really interesting to correlate stem cell activity in tissue culture with the response of the patients."

The work is potentially applicable beyond epilepsy, but first more studies have to be done with larger numbers of patients and more detailed testing of related brain structures and function, the researchers said. In addition, researchers still need to figure out how exactly the newly generated nerve cells contribute to learning and memory.

"The study gives us insights on how to approach the problem of cognitive aging and age-related memory loss, with the hope of developing therapies that can improve cognitive health in the aging," said J. Lee Dockery, M.D., a trustee of the McKnight Brain Research Foundation, which has teamed with the National Institute on Aging to promote research on age-related memory loss.

Scientists are continuing to try to understand just what activates nerve cell production in the brain, and already have begun investigating compounds that might play a role. Animal studies point to a range of possible triggers, but it is difficult to know which are important and which are minor, the researchers said. Because of that, they said, efforts to determine relevant pathways and how to switch them on will be crucial. Noninvasive imaging techniques such as fMRI and PET can help reveal how the process unfolds over time.

"Probably everyone will experience some degree of age-related memory loss as a result of the normal aging process," said Dennis A. Steindler, Ph.D., the executive director of UF's McKnight Brain Institute and one of the study's senior authors. "There is no reason to believe that this is irreversible, and we must find new approaches and therapeutics for allowing everyone to experience productivity and lifelong memory and learning. Facilitating the generation of new functional neurons in our brains throughout life may be one such approach for helping this cause."

Current antiepileptic drugs (AEDs) have many side-effects, among others slowing down brain activity, which in turn reduces patients' ability to react. These side-effects could be eliminated if genes that counteract seizures could be introduced into the brain. Professor Merab Kokaia at Lund University in Sweden has obtained promising results in animal experiments.

Epilepsy is a fairly common condition, affecting around 1 in every 100 people in Sweden. It increases the risk of depression, sudden death, injury and disability. Today's medication not only has side-effects, it is also not sufficiently effective. A large proportion of epilepsy patients are not helped by the drugs and cannot be treated with brain surgery either.

Research in recent years has shown that the brain tries to counteract seizures. One of the ways it does this is by increasing levels of a protein-like molecule called neuropeptide Y and the expression of certain receptors for it.

Both Merab Kokaia's research group and others have previously shown that gene therapy can increase levels of neuropeptide Y in the brain. The Lund researchers are now also the first group in the world to introduce genes that increase the expression of certain receptors for neuropeptides in the brain.

"Neuropeptide Y affects many receptors on the cells in the brain. Some of these increase the risk of seizures and thus have the opposite effect to that which we want to achieve. Therefore it is not ideal to only aim for high levels of neuropeptide Y; we should also ensure that the neuropeptide activates the right receptors," says Merab Kokaia.

He has tested the combined neuropeptide and receptor gene therapy on a rat model of epilepsy and found that the seizures were strongly suppressed. The results have recently been published in the journal Brain.

The genes were introduced into the animals' brains via harmless viruses. These were injected into the specific parts of the brain that are affected by an epileptic condition.

"If the method works on humans, a single treatment would be sufficient, rather than lifelong medication. Unlike current AEDs, such treatment would also only affect the parts of the brain concerned," explains Merab Kokaia.

In the USA the Food and Drug Administration (FDA) is now considering an application to test gene therapy for epilepsy on humans. However, this application only concerns introducing genes to increase expression of neuropeptide Y, whereas the Lund group's findings indicate that genes that increase the expression of the right receptors would be at least as important.

---

Journal Reference:

1. D. P. D. Woldbye, M. Angehagen, C. R. Gotzsche, H. Elbrond-Bek, A. T. Sorensen, S. H. Christiansen, M. V. Olesen, L. Nikitidou, T. v. O. Hansen, I. Kanter-Schlifke, M. Kokaia. Adeno-associated viral vector-induced overexpression of neuropeptide Y Y2 receptors in the hippocampus suppresses seizures. Brain, 2010; DOI: 10.1093/brain/awq219

Chronic pain is a serious medical problem, afflicting approximately 20% of adults. Some individuals are more susceptible than others, and the basis for this remains largely unknown.

In a report published online in Genome Research, researchers have identified a gene associated with susceptibility to chronic pain in humans, signaling a significant step toward better understanding and treating the condition.

The degree of pain experienced after injury or surgery is known to be highly variable between patients, even under nearly identical circumstances, prompting researchers to search for the contribution of genetics to chronic pain susceptibility. To accelerate research in this field, animal models are proving to be critical to understanding the underlying biology of chronic pain in human patients.

Recently, using a mouse model of chronic pain, Ariel Darvasi of the Hebrew University of Jerusalem and colleagues identified a region of mouse chromosome 15 that likely contained a genetic variant or variants contributing to pain. However, this region contains many genes and the responsible variant remained unknown.

Darvasi and an international team of researchers have now undertaken two fine-mapping approaches to narrow down the locus to an interval of 155 genes. Then, by applying bioinformatics approaches and whole genome microarray analysis, they were able to confidently identify a single gene, Cacgn2, as the likely candidate. This gene is known to be involved in cerebellar function and epilepsy, but a functional link to pain had not been described previously.

To further test the potential role for Cacgn2 in chronic pain, the authors utilized a mouse strain harboring a mutant version of the gene that had previously been used in epilepsy research. In testing the mice for behavioral and electrophysological characteristics of chronic pain, they found that, although modest, the observations were consistent with a functional role for Cacgn2 in pain.

However, the question still remained as to whether the human version of the gene, CACGN2, also is important for chronic pain. Analyzing a cohort of breast cancer patients that had undergone removal or partial removal of a breast, they found known genetic polymorphisms in CACNG2 were significantly associated with chronic pain experienced after surgery. The authors cautioned that although this association will need to be analyzed further, the result is encouraging.

"The immediate significance is the mere awareness that differences in pain perception may have a genetic predisposition," Darvasi explained. "Our discovery may provide insights for treating chronic pain through previously unthought-of mechanisms."

Scientists from The Hebrew University of Jerusalem (Jerusalem, Israel), the University of Toronto (Toronto, Canada), Sanofi-Aventis Germany (Frankfurt am Main, Germany), and the Karolinska Institute Center for Oral Biology (Huddinge, Sweden) contributed to this study.

This work was supported by the Israel Science Foundation, The Hebrew University Center for Research on Pain, the Canada Research Chair Program, and the European Community's 6th Framework Program.

---

Journal Reference:

1. Nissenbaum J, Devor M, Seltzer Z, Gebauer M, Michaelis M, Tal M, Dorfman R, Abitbul-Yarkoni M, Lu Y, Elahipanah T, delCanho S, Minert A, Fried K, Persson A, Shpigler H, Shabo E, Yakir B, Pisante A, Darvasi A. Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2. Genome Research, 2010; DOI: 10.1101/gr.104976.110

Scientists are reporting a possible explanation for the bone loss that may occur following long-term use of a medicine widely used to treat epilepsy, bipolar disorder, and other conditions. The drug, valproate, appears to reduce the formation of two key proteins important for bone strength, they said. Their study, which offers a solution to a long-standing mystery, appears in ACS' Journal of Proteome Research.

Glenn Morris and colleagues point out that use of valproate, first introduced more than 40 years ago for the prevention of seizures in patients with epilepsy, has expanded. Valproate now is prescribed for mood disorders, migraine headache, and spinal muscular atrophy (SMA), a rare genetic disease that causes loss of muscle control and movement. Many SMA patients develop weak bones as a result of the disease itself, making further bone loss from valproate especially undesirable. Doctors have known about the bone-loss side effect, but until now, there has been no molecular explanation.

In an effort to determine why bone loss occurs, the scientists profiled valproate's effects on more than 1,000 proteins in the cells of patients with SMA. They found that valproate reduced production of collagen, the key protein that gives bone its strength, by almost 60 percent. The drug also reduced levels of osteonectin, which binds calcium and helps maintain bone mass, by 28 percent. "The results suggest a possible molecular mechanism for bone loss following long-term exposure to valproate," the article notes.

---

Journal Reference:

1. Fuller et al. Valproate and Bone Loss: iTRAQ Proteomics Show that Valproate Reduces Collagens and Osteonectin in SMA Cells. Journal of Proteome Research, 2010; 100722144125012 DOI: 10.1021/pr1005263

New research points to a genetic route to understanding and treating epilepsy. Timothy Jegla, an assistant professor of biology at Penn State University, has identified an ancient gene family that plays a role in regulating the excitability of nerves within the brain.

The research appears in the journal Nature Neuroscience.

"In healthy people, nerves do not fire excessively in response to small stimuli. This function allows us to focus on what really matters. Nerve cells maintain a threshold between rest and excitement, and a stimulus has to cross this threshold to cause the nerve cells to fire," Jegla explained. "However, when this threshold is set too low, neurons can become hyperactive and fire in synchrony. As excessive firing spreads across the brain, the result is an epileptic seizure."

Managing this delicate rest-excitement balance are ion channels — neuronal "gates" that control the flow of electrical signals between cells. While sodium and calcium channels help to excite neurons, potassium channels help to suppress signaling between cells, increasing the threshold at which nerves fire. However, the genetic mechanisms that control the potassium channels and set this threshold are not fully understood. Jegla's team focused on a particular potassium-channel gene — called Kv12.2 — that is active in resting nerve cells and is expressed in brain regions prone to seizure.

"We decided that Kv12.2 was a good candidate for study because it is part of an old gene family that has been conserved throughout animal evolution," Jegla said. "This ancient gene family probably first appeared in the genomes of sea-dwelling creatures prior to the Cambrian era about 542-million years ago. It is still with us and doing something very important in present-day animals." Previous studies have suggested that the Kv12.2 potassium channel has a role in spatial memory, but Jegla and his team focused on how it might be related to seizure disorders.

In collaboration with Jeffrey Noebels at Baylor College of Medicine, the team used an electroencephalography (EEG) device to monitor the brains of mice. They found that mice missing the Kv12.2 gene did indeed have frequent seizures, albeit without convulsions. The team then stimulated mice with a chemical that induces convulsive seizures. They found that normal mice had a much higher convulsive-seizure threshold than mice with a defective Kv12.2 gene. The team also found the same results when they used a chemical inhibitor to block the Kv12.2 potassium channel in normal mice.

"In mice without a functioning Kv12.2 gene, nerve cells had abnormally low firing thresholds. Even small stimuli caused seizures," Jegla explained. "We think that this potassium channel plays a role in the brain's ability to remain 'quiet' and to respond selectively to strong stimuli."

Jegla hopes to open up new avenues of epilepsy research by studying whether activation of the Kv12.2 potassium channel in normal animals can block seizures. "Ion-channel defects have been identified in inherited seizure disorders, but many types of epilepsy don't have a genetic cause to begin with," Jegla explained. "They are often caused by environmental factors, such as a brain injury or a high fever. However, the most effective drugs used to treat epilepsy target ion channels. If we can learn more about how ion channels influence seizure thresholds, we should be able to develop better drugs with fewer side effects."

In addition to Jegla and Noebels, other scientists who contributed to this research include Xiaofei Zhang, Federica Bertaso, Karsten Baumgärtel, and Sinead M. Clancy of the Scripps Research Institute; Jong W. Yoo of the Baylor College of Medicine; and Van Lee, Cynthia Cienfuegos, Carly Wilmot, Jacqueline Avis, Truc Hunyh, Catherine Daguia, and Christian Schmedt of the Genomics Institute of the Novartis Research Foundation. This research was funded by the National Institutes of Health through its National Institute for Neurological Disorders and Stroke.

---

Journal Reference:

1. Xiaofei Zhang, Federica Bertaso, Jong W Yoo, Karsten Baumgärtel, Sinead M Clancy, Van Lee, Cynthia Cienfuegos, Carly Wilmot, Jacqueline Avis, Truc Hunyh, Catherine Daguia, Christian Schmedt, Jeffrey Noebels & Timothy Jegla. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nature Neuroscience, 2010; DOI: 10.1038/nn.2610

A chemical compound that boosts the action of a molecule normally produced in the brain may provide the starting point for a new line of therapies for the treatment of epileptic seizures, according to a new study by scientists at The Scripps Research Institute.

"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 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.

Enter Galanin

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 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.

This study was supported by the National Institutes of Health.

---

Journal Reference:

1. Xiaoying Lu, Edward Roberts, Fengcheng Xia, Manuel Sanchez-Alavez, Tianyu Liu, Roger Baldwin, Stephanie Wu, James Chang, Claude G. Wasterlain, and Tamas Bartfai. GalR2-positive allosteric modulator exhibits anticonvulsant effects in animal models. Proceedings of the National Academy of Sciences, 2010; DOI: 10.1073/pnas.1008986107