Danger Signaling, Traumatic Brain Injury, and Epileptogenesis
Abstract
It is now well recognized that the inflammation plays an important role in the brain’s response to traumatic injury. A substantial body of evidence also supports a key role for inflammation in epileptogenesis, the pathological process that leads to the development and progression of spontaneous recurrent epileptic seizures. This application focuses on the activation of the immune system in the first 7 days from the time of injury. Initially, damaged brain tissue releases danger signals, molecules that help to recruit immune cells to the site of injury and to activate them. These cells themselves release more danger signals thus amplifying the recruitment and activation process. Although the immune system contributes to the removal of dead cells and to tissue repair, we postulate that an exaggerated and prolonged response resulting from the excessive release of danger signals within a short timeframe in traumatic brain injury contributes to secondary damage, the expansion of damage beyond the initial injury, and to epileptogenesis. Many of the molecular danger signals activate common pathways when they bind to receptors on immune cells. While these receptors could be points at which excessive danger signaling may be inhibited, there are many of them. To counter this in-built redundancy in danger signaling, we have identified a co-receptor (helper molecule), named CD14, which is required for the activation of many signaling pathways. Our objective is to examine the effect of blocking CD14 on the development of epilepsy after traumatic brain injury. Studies will be undertaken in the mouse controlled cortical impact brain injury model, a well-validated preclinical model of traumatic brain injury and post-traumatic epilepsy. We will use video monitoring combined with an electroencephalogram to detect the development of epilepsy. Effects on inflammation and secondary damage will be assessed using a combination of imaging and inflammatory molecule profiling and effects on functional outcome will be evaluated using behavioral tests. Our research strategy is designed to meet several challenges to future clinical translation. • We focus on a CD14 blocking agent that is already far-advanced in its development for the treatment of other diseases. For this agent, human testing, pharmacology, and toxicity have already been extensively evaluated, allowing successful outcomes from preclinical studies to be rapidly translated to clinical trials. • Blocking CD14 has multiple and broad-ranging anti-inflammatory actions, making it more likely to be effective than therapies with more restricted anti-inflammatory targets because traumatic brain injury activates multiple inflammatory pathways. • We will use the imaging techniques of magnetic resonance imaging and positron emission tomography to assess secondary brain damage, activation of inflammatory cells and disruption of the barrier between blood and brain. Assays of CD14 in the blood will also be performed. This work will contribute to the development of robust biomarkers that could allow the treatment regimen to be precisely tailored to the individual patient.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110444
Entities
People
- David C. Reutens
Organizations
- United States Army
- University of Queensland