Michael Wong, MD, PhD
Washington University, St. Louis, MO

“Stabilizing Dendritic Structure as a Novel Treatment for Epilepsy”

Injury to the brain caused by repeated seizures may contribute to cognitive dysfunction and other neurological deficits in epilepsy patients. In this three-year project, Dr. Wong will investigate the direct effects of seizures on dendrites and dendritic spines, which are key components of synapses and potential sites of learning and memory in the brain. He will utilize modern cellular imaging techniques to visualize structural changes in dendrites in mice before and after seizures. The molecular mechanisms underlying these changes during seizures will be explored. Finally, drugs that can inhibit this dendritic injury will be tested, potentially leading to novel treatments for preventing seizure-induced brain injury.

Steven L. Bealer, PhD
University of Utah, Salt Lake City, UT

“Predictors of Cardiac Risk and Beneficial Effects of Pharmacotherapy in Epilepsy”

In patients with epilepsy, sudden cardiac death may occur following status epilepticus (prolonged seizures), in sudden unexplained death in epilepsy (SUDEP), and in patients with epilepsy and co-existing cardiac disease. However, the relationship between epilepsy, clinical indicators of cardiac risk, and the beneficial effects of drugs that protect the heart are not known. In this three-year project, Dr. Bealer will evaluate these relationships to determine which patients should be routinely evaluated for cardiac risk, and whether appropriate cardiac drug therapy reduces the risk of death.

Dmytro Isaev, PhD
Bogomoletz Institute of Physiology, Kiev, Ukraine

Gregory L. Holmes, MD
Dartmouth Medical School, Lebanon, NH

“Reduction in Seizure Susceptibility through Modification of the Level of Extracellular Sialic Acid”

Far too many individuals with epilepsy who take antiepileptic drugs continue to have seizures or suffer from serious medication side effects. Working together, Dr. Holmes (a pediatric neurologist) and Dr. Isaev (a senior researcher in general physiology of the nervous system) recently showed that they could dramatically reduce seizures by altering a naturally occurring compound in the brain called sialic acid. By reducing sialic acid, they have been able to turn down “the thermostat of the brain,” reducing brain excitability without causing any substantial side effects. In this one-year study, Drs. Holmes and Isaev will build upon these exciting preliminary results and determine whether modification of sialic acid reduces seizures in a mouse model of epilepsy and prevents the onset of epilepsy following brain injury.

Gregory Mathews, MD, PhD
Vanderbilt University Medical Center, Nashville, TN

David Poulsen, PhD
University of Montana, Missoula, MT

“Targeted Enhancement of GABA Synthesis for Epilepsy Therapy”

Despite a dramatic increase in new drugs available for epilepsy patients, more than 30% of patients still do not achieve seizure freedom. Therapies aimed at increasing GABA, the major neurotransmitter in the brain, are key targets for anticonvulsant therapies. However, traditional medications are heavily sedating with significant cognitive side effects. This one-year collaborative effort between Dr. Poulsen (a molecular virologist) and Dr. Mathews (a clinical epileptologist and basic neuroscientist) will explore the use of viral gene technology for enhancing GABA, offering the promise of new and less debilitating therapeutic options for epilepsy patients.

Christophe Bernard, PhD
INSERM, Marseille, France

“Dendritic HCN Channels as a Target against Epileptogenesis and for Improving Cognitive Deficits in Temporal Lobe Epilepsy”

In addition to seizures, many patients with epilepsy struggle with memory and other cognitive deficits. Dr. Bernard has shown that temporal lobe epilepsy is associated with a loss of function of a specific protein in the brain called hyperpolarizing-activated cyclic nucleotide-gated ion channels (HCN). This loss not only makes the cell more excitable but also impairs cognitive function. In this study, Dr. Bernard’s goal is to determine whether the loss of HCN may actually cause epilepsy and/or cognitive dysfunction. By boosting HCN activity in animal models of epilepsy, using specific drugs or via genetic technology, this study may lead to new approaches to controlling seizures with the potential of also restoring cognitive function.

Karin Borges, PhD
Texas Tech University Health Sciences Center, Amarillo, TX

“Anaplerosis: A Potential New Dietary Therapy for Epilepsy”

Many patients with epilepsy do not respond to drugs or to the high-fat ketogenic diet. Triheptanoin, a tasteless and well-tolerated oil, is a component of the anaplerotic diet. This oil is believed to provide more energy to the brain, which may help to stabilize nerve cell activity and prevent seizures. In this one-year study, Dr. Borges will test, in mice, whether an anaplerotic diet can inhibit seizures. If so, this study could lay the groundwork for future investigation of this novel approach to treating epilepsy.

David Prince, MD
Kevin Graber, MD, co-investigator - Stanford University, Stanford, CA

Prevention of Neocortical Post-traumatic Epileptogenesis

There is often a delay between brain injury and development of seizures in lab animals and in humans. Dr. David Prince has shown that development of post-traumatic epilepsy in animals can be prevented by briefly treating the injured brain with a substance that blocks nerve cell messages. In this two-year study, they will use other approaches, such as the application of a drug that acts to decrease the action of an excitatory messenger normally pr esent. Other experiments will test whether increases in a gene that prevents both nerve injury and development of new connections will prevent post-traumatic epilepsy in animals. This grant is jointly sponsored by the USAMRMC and funds raised from the Northwestern University 2007 Dance Marathon.

Detlev Boison, PhD
Theresa Lusardi, PhD, co-investigator - RS Dow Neurobiology Lab, Legacy Research Portland, OR

Prevention of Posttraumatic Epilepsy by Transient Modulation of Adenosine Receptors

Adenosine is one of the brain’s own seizure-control substances and recent evidence suggests that epilepsy development is associated with a failure in the adenosine system. A frequent cause for the development of epilepsy is a previous traumatic brain injury. In this two-year study, Dr. Boison will examine how failures in the adenosine system develop as a consequence of brain injury, how these failures contribute to the development of spontaneous recurrent seizures, and how the development of epilepsy can be prevented by transient application of adenosine-related drugs during a critical window of time after the injury.

Daniela Kaufer, PhD
Alon Friedman, MD, PhD, co-investigator - University of California, Berkeley, CA

The Role of Serum Albumin and TGF-Beta in Post-Traumatic Epileptogenesis

The mechanism by which traumatic brain injury leads to epilepsy is mostly unknown and, at present, no preventive treatment exists. Dr. Kaufer, along with co-investigator Dr. Alon Friedman of Ben-Gurion University of the Negev Beer-Sheva in Israel, discovered a novel mechanism that occurs following the injury-induced breakdown of the blood-brain barrier, leading to the development of epilepsy. This process is dependent on specific uptake of the serum protein albumin into the "supporting" cells of the brain, known as astrocytes. This two-year project aims to develop therapies that will prevent the generation of epilepsy following brain trauma.

Jian Kang, MD, PhD - New York Medical College, New York, NY

Roles of Glutamate-Induced Astrocytic Glutamate Release in Post-Traumatic Epilepsy

Post-traumatic epilepsy is a common neurological disorder following brain injury. The cellular and molecular mechanism of this disease is still unknown. The goal of this two-year project is to study how glutamate release from astrocytes, the “supporting” cells of the brain, causes the development of post-traumatic epilepsy. In response to increased extracellular glutamate, astrocytes release a large amount of glutamate through fusion of a large vesicle. This may contribute to the cellular mechanism of post-traumatic epilepsy. This work may lead to a novel target for preventing post-traumatic epilepsy following brain injury.

Adi Mizrahi, PhD - The Hebrew University of Jerusalem, Israel

In Vivo Time-Lapse Imaging of an Epileptogenic Focus in Post-Traumatic Epilepsy

In this three-year project, Dr. Mizrahi will study the changes within the brain that underlie the development of post-traumatic epilepsy in mice. He will use live imaging techniques in a mouse model of post-traumatic epilepsy to learn how brain cells react when post-traumatic epilepsy develops. These experiments will provide a direct view, at high resolution, of the actual dynamics of the development of epilepsy. Such in vivo experiments may lead to the discovery of new biological mechanisms that lead to epilepsy after brain injury.

Philip Schwartzkroin, PhD - University of California, Davis, CA

Dietary and Activity Treatments for Modulating Post-Traumatic Brain Hyperexcitability

In this two-year project, Dr. Schwartzkroin will study potential protective therapies in a rat model of traumatic brain injury. He will examine the effects of a ketogenic diet administered both before and after the brain insult, including the potential addictive effects of the diet. In addition, because “enriched environment therapies” have been shown to promote the birth of new brain cells, Dr. Schwartzkroin will study the effects of exposure to such environments. If these simple and inexpensive treatments can reduce the expected brain cell damage associated with traumatic brain injury, and/or prevent the development of abnormal brain excitability, then these therapies could be applied to humans after traumatic brain injury (e.g., soldiers who have received head trauma in conflict).

Anne Anderson, MD & Matteo Vatta, PhD - Baylor College of Medicine / Houston, TX

CENTRAL NEW YORK AWARD, In memory of Christopher Donalty and Kyle Coggins

Myocardial Ion Channel Remodeling: A Candidate Mechanism for Sudden Death in Epilepsy

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of mortality in individuals with epilepsy. This study hypothesizes that cardiac ion channels may be affected by primary genetic or acquired alterations associated with epilepsy, which represent candidate mechanisms in SUDEP. Cardiac ion channel alterations due to either of these mechanisms would predispose the heart to arrhythmia, which is a risk factor for sudden death. The studies will be performed as an interdisciplinary collaboration between Dr. Anderson, an epilepsy researcher, and Dr. Vatta, a cardiovascular researcher with expertise in myocardial remodeling and channelopathies. The interdisciplinary approach between the fields of epilepsy and cardiovascular sciences represents a novel and unprecedented opportunity in the field of epilepsy research and specifically in the area of SUDEP.

Carl Faingold, PhD & Victor Uteshev, PhD - Southern Illinois University School of Medicine / Carbondale, IL

SUDEP Prevention - Experimental Serotonergic Mechanisms in DBA/2 Mice

Sudden unexpected death in epilepsy (SUDEP) results from breathing failure after seizures. The DBA/2 mouse model also shows seizures and death due to breathing failure. Fluoxetine, a drug which increases the brain chemical serotonin, prevents breathing failure in DBA/2 mice. This collaborative project between Dr. Faingold, an epilepsy researcher and Dr. Utsehev-Gaard, a basic neuroscientist, will determine if novel drugs acting on serotonin will block SUDEP in DBA/2 mice with lower doses and fewer side effects. They will also examine how these drugs act on a brain region (solitary tract nucleus), which controls breathing to observe the nature of the defect causing death in DBA/2 mice.

Scott Baraban, PhD & John Rubenstein, MD, PhD - University of California/ San Francisco, CA

RHODE ISLAND AWARD

GABA progenitor cells as a treatment of epilepsy disorders

Transplantation of neuronal progenitor or “stem cells” offers great promise for developing an epilepsy cure. Because transplanted progenitors can migrate and integrate as new neurons in the host brain, manipulation of these cells could be a powerful means to stop seizures before they start. Dr. Baraban’s lab has developed a method to transplant embryonic progenitor cells that integrate exclusively as inhibitory interneurons. In a parallel study, they developed a mouse mutant characterized by interneuron loss, reduced inhibition and late-onset epilepsy. Combining the expertise of Dr. Baraban, an established epilepsy investigator and Dr. Rubenstein, a world-expert on interneuron development, this CURE study will combine these two projects into a critical “proof-of-principle” trial aiming to determine whether transplanted GABA-progenitor cells restore normal levels of inhibition and rescue these mutant mice from developing epilepsy. This study is a necessary next step toward development of appropriate clinical treatments utilizing progenitor cells.

Julie Blendy, PhD, University of Pennsylvania, Philadelphia, PA & Brenda Porter, MD - Children’s Hospital of Philadelphia, Philadelphia, PA

2007 NORTHWESTERN DANCE MARATHON AWARD

The Role of CREB in Epileptogenesis

The goal of this project is to identify cellular and molecular changes that contribute to the development of epilepsy after an injury to the brain. A large number of molecular, cellular and physiologic changes have been described following brain injury, including neuronal cell loss, and changes in the expression of genes and proteins. Dr. Porter, an epilepsy researcher, and Julie Blendy, a pharmacologist will examine whether one of the master regulators of neuronal survival and gene expression, CREB, is necessary for animals to develop epilepsy after brain injury.

Douglas Nordli, MD - Children’s Memorial Hospital, Chicago, IL
In collaboration with: William Gaillard, MD – George Washington University Medical School, Washington, DC & Helen Cross, MD, PhD – Great Ormond Street Hospital for Children, London England

Pediatric Epilepsy Database Consortium

Lionel Carmant, MD - CHU-Sainte-Justine, Montreal, Canada

Preventing Autism and Other Long-term Complications of Infantile Spasms (IS)

Infantile spasms are a catastrophic form of epilepsy, because they are associated with an arrest or even a regression in the physical and mental development of children affected. More than 80% of children become mentally retarded and more than 10% develop autistic behaviors. In previous studies, children received a standard protocol of vitamin B6 and high dose vigabatrin for six months, except those with persistent spasms or EEG abnormalities at two weeks, who administered high dose steroids. In addition, in a double-blind manner, children received the neuroprotective treatment (flunarizine) versus placebo. In this two year study, Dr. Camant will evaluate whether this neuroprotective treatment improved long-term outcome by performing a developmental evaluation at 24 months and another one at 30 months post-diagnosis for autism. If preliminary results prove to be correct, Carmant anticipates that children treated with flunarizine will be more likely to develop normally and less likely to develop autism.

Gabriella D’Arcangelo, PhD - Rutgers University, Piscataway, NJ

JULIE'S HOPE AWARD (partial scholarship)

Generation and Characterization of Mouse Models of Cortical Dysplasia

Epilepsy affects approximately one in every 100 children, and over 30% of these patients cannot be controlled with traditional antiepileptic treatments. Many of these children are found to have malformations of the cerebral cortex (cortical dysplasia).  As a first step towards finding a cure for this type of epilepsy Dr. D’Arcangelo will create genetically engineered mice as animal models for cortical dysplasia.  This new mouse model will be based on the abnormal activation of the PI3K signaling pathway in dysplastic brain cells. In this three year study, the model will be used to test the effectiveness of specific inhibitors of this pathway which will potentially lead to new antiepileptic agents.

Nicholas Poolos, MD, PhD - University of Washington / Seattle, WA

THE MATTHEW SIRAVO MEMORIAL AWARD

Kinase Mediation of Antiepileptic Drug Action

Many of the antiepileptic drugs (AEDs) in clinical use today have mechanisms of action that remain unclear. One AED in particular, lamotrigine, appears to lack a direct action on the ion channel (the HCN channel) that may be responsible for its effectiveness across a broad spectrum of seizure types. Dr. Poolos will investigate the novel hypothesis that lamotrigine may regulate HCN channels not by direct interaction, but instead by altering the behavior of intracellular enzymes (kinases) that in turn control ion channel activity. If this hypothesis is proven, it will suggest new pathways for development of improved drugs against epilepsy.

Dwayne W. Godwin, PhD - Wake Forest University School of Medicine / Winston-Salem, NC

THE CURE 365 AWARD

Metabotropic Glutamate Receptors - a Strategic Target for Novel Antiepileptic Therapeutics

Epilepsy is a chronic neurological disorder characterized by seizures that involve specific systems of the brain in the case of partial seizures, or seizures that may start in a restricted region of the brain but spread, or generalize, to involve other regions. Glutamate is the predominant excitatory neurotransmitter in the brain, and has a fundamental role in the communication of activity, whether that activity is normal or abnormal. Dr. Godwin’s research is focused on a class of glutamate receptors called metabotropic glutamate receptors. These receptors modulate the release of glutamate, and can selectively suppress hyperactive synapses. Dr. Godwin  plans to  strategically target a specific type of metabotropic receptor that reduces glutamate release at the key sites in the brain where seizures start and spread. By taking advantage of selective pharmacological agents, he hopes to stop or impede the generation of seizures before they start. The modulatory nature of these targets may provide new pharmacological treatment options with fewer side effects than are observed in currently prescribed anti-epileptic drugs, and may be helpful to individuals whose seizures may be resistant to current treatments.

Janet Soul, MD, CM - Children’s Hospital Boston and Harvard Medical School/ Boston, MA

THE GRAHAM GODDARD YOUNG INVESTIGATOR AWARD (sponsored by an unrestricted educational grant from UCB Pharma)

Pilot Study of Bumetanide For Refractory Neonatal Seizures

Newborn babies have seizures much more frequently than either children or adults, and their seizures are often associated with serious long-term consequences such as epilepsy, learning disabilities and cerebral palsy. Although newborn seizures are very common, medications currently used to treat them are relatively ineffective and may have serious side effects.  A medication called bumetanide shows great promise for treating newborn seizures because the drug blocks special channels present only in the brain cells of newborns. We will conduct a pilot trial to determine whether bumetanide is a safe drug for the treatment of newborn seizures.