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).

Raimondo D'Ambrosio, PhD - University of Washington, Seattle, WA

Prophylaxis of posttraumatic epilepsy following head injury in the rat

Posttraumatic epilepsy is a chronic neurological disorder that appears following head injury and for which there currently is no prophylactic treatment. This project aims to achieve two goals by employing our recently developed model of posttraumatic epilepsy, in which chronic recurrent spontaneous partial seizures reliably appear in the rat following a realistic insult (FPI) presenting mechanical features very similar to human closed head injury. First, we aim to examine acute and subacute electrocorticograms to determine whether an electrophysiological biomarker of epileptogenesis exists that would allow one to predict the later onset of epilepsy. Such a biomarker would allow one to target antiepileptogenic treatments to patients at risk of developing epilepsy and not to others, therefore reducing side effects. Second, we aim to begin testing the effectiveness of drugs that already have an excellent human safety profile and that are currently being considered for clinical trial of antiepileptogenesis following head injury. Our work will help optimize these clinical trials and increase their chances of success.

Maiken Nedergaard, MD, PhD - University of Rochester, Rochester, NY

Post traumatic epilepsy – targeting reactive gliosis

This project offers a new conceptual and operational approach to understanding the cellular basis of seizure disorders. If a dysregulation in astrocytic Ca2+ signaling indeed proves causal in epileptogenesis – as our data strongly suggest – then the implications of this new perspective to pharmacotherapy could be profound. The often imprecise correlation of anti-epileptogenic activity with synaptic suppression would be better understood, allowing new emphasis on therapeutic strategies intended to screen for agents able to suppress astrocytic Ca2+ signaling and/or glutamate release.

Asla Pitkänen, MD, PhD, DSci - University of Kuopio, Finland

Post-traumatic epileptogenesis: Development and use of animal models for identification of molecular mechanisms and surrogate markers

Traumatic brain injury (TBI) is a major cause of acquired focal epilepsy in adults. This projects aims at developing new, clinically relevant animal models that can be used to investigate molecular mechanisms of epileptogenesis after TBI and to test novel candidate treatments for prevention of post-traumatic epilepsy (PTE). The second goal is to find surrogate markers that could identify the subjects who are at risk of developing PTE by using magnetic resonance imaging.

Matthew Smyth, MD - Washington University, St. Louis, MO
Raimondo D'Ambrosio, PhD, co-investigator - University of Washington, Seattle, WA

Evaluation of focal cortical cooling to prevent epileptogenesis and control chronic seizures induced by fluid percussion injury in the rat

The aim of our proposal is to evaluate the effects of focal brain cooling on treating and preventing post-traumatic seizures. This proposal follows the initial discovery and description of electrical and behavioral partial seizures following fluid-percussion injury (FPI) in the rat. Focal brain cooling may provide a novel therapeutic model to treat medically refractory seizures without tissue destruction inherent in surgical resections and disconnections. Because of the similarities existing between this rodent model and human post-traumatic epilepsy (PTE), the data collected during this project will determine whether focal cooling may lead to improved therapy for acquired human epilepsy. The experiments planned include the administration of direct focal cooling at the FPI site after the development of post-traumatic chronic seizures in order to evaluate the anti-seizure effect of focal cortical cooling. Experiments also planned include the evaluation of the magnitude and extent of cooling on surrounding brain tissue, the temperatures required to inhibit seizure activity, and the potential neurotoxic effects of focal cooling. Obtaining these data will be an instrumental first step toward the translation of this technology in clinical settings.

Scott Thompson, PhD - University of Maryland School of Medicine, Baltimore, MD

Preventing Denervation-induced Hyperexcitability After Traumatic CNS Injury

A traumatic brain injury causes several disorders that are characterized by the delayed occurrence of changes in brain function, such as posttraumatic epilepsy. Because brain injuries are complicated, we have developed a simplified experimental approach that allows us to look at one particular consequence of brain injury in isolation, namely the loss of normal input after nerve pathways are severed during an injury. We have evidence that the brain cells that lose their normal inputs try to compensate for the lack of normal activity. Unfortunately, that this ‘sensible’ response of the cells results in an unintended consequence- epilepsy. Using laboratory rats, we will be testing the mechanisms that the cells use to compensate for the lack of activity and also test a class of medicines that may counteract those changes. We hope that our work will lead to novel treatments that can prevent the development of epilepsy after brain injury.