Developing Small Molecule Therapeutics for Preventing Post-Traumatic Epilepsy
Abstract
Post-traumatic epilepsy (PTE) is characterized by frequent, severe seizures following traumatic brain injury (TBI). Approximately 50% of those suffering penetrating brain injuries will develop PTE. This disorder is a major concern for our military forces and Veterans, due to the increasing incidence of head injuries suffered in battle during the Global War on Terror. In fact, 440,000 Soldiers from the Iraq and Afghanistan wars have had or will experience TBI, of which more than 100,000 are likely to develop PTE. Adding to the disease burden, there is no cure for PTE; symptoms are often resistant to traditional treatments, which are currently limited to anticonvulsants that can only treat the seizures once they develop. Moreover, even when such therapies are effective, many have severe side effects. Progress towards more effective treatments, including those that may prevent PTE before it starts, are limited by our lack of understanding of pathogenic mechanisms at the cellular and circuit levels. Our long-term goal is to develop therapeutic strategies that control seizures and/or prevent the development of epilepsy, while causing minimal side effects. Following TBI, there are changes to the properties and connections among the neurons in the area of acute injury, i.e., the cortex. The cortex is the outermost region of the brain and is thus usually involved in the primary brain injury. However, the initial damage has ramifications for deeper, more distant brain regions that may be secondarily damaged via their cellular connections to the initial injury site. This secondary damage occurs over the course of weeks, the so-called latent phase, as maladaptive changes propagate through several different cell types in the brain, including brain cells, blood vessel cells, and support cells, and eventually leads to PTE. The thalamus, located deep in the brain but extensively connected to regions all over the cortex, is one of the structures most prone to this secondary damage. Although there have been no studies directly linking thalamic damage to PTE, accumulating evidence implicates the thalamus in pathogenic mechanisms linking cortical lesions to epilepsy. There are several reasons to believe that the thalamus is involved in the development of PTE. First, PTE patients often have problems with attention, sensation, perception, consciousness, and sleep, which are all functions mediated by the thalamus. Second, there is an increase in the number of inflammatory molecules (key indicators of cellular damage) present in the thalamus after TBI. Third, brain cells in the thalamus die or become abnormal after injury to the cortex, and the electrical activity of the thalamus also changes. Finally, suppressing activity in brain cells of the thalamus can control seizures resulting from cortical damage. Our own preliminary findings further demonstrate that the secondary damage in the thalamus is due to brain cell death caused by: (1) the loss of cortical connections to the injury site and (2) further inflammation induced by the maladaptive accumulation of astrocytes, a support cell in the brain. We have shown that these key factors increase seizure susceptibility in rodents who have sustained acute cortical injury. In a recent collaboration with Dr. Sheng Ding, we found several small molecule drugs that can be easily delivered into the brain and target these two sources of thalamic damage. Here, we propose to build on this prior work through a multipronged approach that tests the efficacy of these drugs in preventing post-TBI epileptogenesis. We will test the efficacy of two small molecule drugs: RA8, which specifically targets the accumulation of inflammatory astrocytes; and SM2, which works to prevent cell death due to the loss of connections to the injured cortical region. We will determine whether each drug on its own can effectively reduce seizure susceptibility in mice following acute cortical injury (a mouse mo
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010160
Entities
People
- Jeanne T. Paz
Organizations
- The J. David Gladstone Institutes
- United States Army