Targeting Complement in Post-Traumatic Epileptogenesis
Abstract
It is now well recognized that the inflammation plays an important role both in the brain’s response to traumatic injury and in the subsequent development of epilepsy. The complement system comprises a number of proteins that have broad-ranging effects on the inflammatory response. Our objective is to examine the effect of therapies that target activation of the complement system on the development of epilepsy after traumatic brain injury. Studies will be undertaken using a mouse controlled cortical impact brain injury model. We will study several complement-targeting agents that are already approved for human use or are well advanced in their development. One of these is intravenous immunoglobulin, which our preliminary data show attenuates inflammation and improves functional outcome after traumatic brain injury. Studying the effects of agents blocking different points in its activation pathway will yield a fine-grained understanding of complement’s involvement in the development of epilepsy. Our research strategy is designed to meet several challenges to future clinical translation. By focusing on therapies that are already approved for human use or far advanced in their development, we have adopted a drug repurposing approach. For these agents, human testing, pharmacology, and toxicity have already been extensively evaluated, allowing successful outcomes from preclinical studies to be rapidly translated to clinical trials. Therapies targeting complement have multiple and broad-ranging anti-inflammatory actions. These are 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 (MRI) and positron emission tomography (PET) to assess secondary brain damage, activation of inflammatory cells, and disruption of the barrier between blood and brain. This work will contribute to the development of robust biomarkers that could allow anti-inflammatory treatment regimens to be precisely tailored to the individual patient.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710670
Entities
People
- David C. Reutens
Organizations
- United States Army
- University of Queensland