Novel Strategies Targeting Signaling Molecules of Neurons and Astrocytes to Prevent Acquired Epilepsies
Abstract
Traumatic brain injury (TBI) is a common experience in the military and civilian population, from battlefield incidents, vehicular accidents, and falls. Immediately after a TBI, a number of changes occur in the brain that cause brain damage, seizures, and the development of epilepsy. Some of them are due to the loss of proper oxygen and nutrients, such as seen during a stroke, resulting in cell death, leakage of blood into brain tissue, and an inflammatory response that further exacerbates the trauma. Although a post-trauma seizure (PTS) is not desirable, the larger problem is that a PTS causes changes in the brain that make it more likely to have continued seizures, leading to the development of long-term repetitive seizures, which is called epilepsy. It has been shown that over 6% of all epilepsy originates from TBIs. Along with development of epilepsy often comes concurrent anxiety and depression, all of which causes severe reduction in the post-TBI quality of life. Surprisingly given the scope of the problem, acute treatment to prevent this tragic series of events is only beginning to be explored. We seek to prevent this deleterious cascade by targeting two proteins -- one called a potassium ion channel found on the surface of nerve cells and another a receptor that is found on cells called astrocytes. Activity of the potassium channel acts as a "brake" on nerve cell hyperexcitability and resulting "excitotoxicity" that worsens brain trauma. Astrocytes are the most abundant cell type in the human brain; nerve cell viability and survival depend on them. Using a Food and Drug Administration-approved drug that is an "opener" of nerve cell potassium channels and an agonist of the astrocyte receptor, we will test the hypothesis that we can prevent the myriad types of harmful brain damage by acutely administering these drugs within 3 hours of a TBI. Our approach uses two mouse TBI models. The first involves a pneumatic impact device that simulates a blunt-trauma TBI. The second is a "blast tube" that simulates a blast TBI such as experienced by military personnel subjected to explosions on the battlefield. The read-outs of epilepsy development brain injury will include live-animal video recording and EEG (electroencephalography) monitoring, in which clinical or sub-clinical seizure activity can be assayed and scored. We will also test for changes in seizure susceptibility after an initial seizure, much like epilepsy development following a PTS. Using brain-slice analysis, we will look for changes in brain morphology and brain chemistry that are associated with epileptogenesis. Finally, we will utilize a battery of behavioral tests that measure anxiety, fear, and depressive behaviors that often accompany PTS and development of epilepsy. All these tests will compare responses in control animals subjected to TBIs without being treated with drugs to the responses of animals administered with ion-channel and receptor-targeting drugs. The project brings together a highly complementary and innovative team of researchers. Applicability of Research: The findings of our research could soon lead to rapid treatments for Service members and civilians affected by TBIs. These treatments could also minimize long-term problems associated with TBI including development of epilepsy and changes in psychological behavior. The proposed pharmacological therapies would allow injured Service members or civilians immediate treatment on the battlefield or the scene of an accident, without the requirement of trained medical personnel beyond the usual training of first-responders. Acute systemic introduction of drugs by intravenous injections would be possible with limited facilities and without any specialized equipment. Our preliminary studies demonstrate that our treatment strategies significantly reduce cellular and brain edema in a mouse model of TBI, one of the signature hallmarks of seizure likelihood. The experiments in
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510283
Entities
People
- James D Lechleiter
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio