Photosensitivity as a Biomarker for Treatment of Chronic Post-Traumatic Headache
Abstract
The proposed research addresses Fiscal Year 2015 Peer Reviewed Medical Research Program Topic Area "Chronic migraine and post-traumatic headache." The Gap/Priority Area will be to investigate, develop, and validate biomarkers. The overall objective of this proposal will be to develop an objective biomarker and treatment to reverse post-traumatic headache (PTH). Unfortunately, PTH is highly prevalent in active duty personnel and Veterans following traumatic brain injury (TBI). The high incidence and chronic nature of PTH underscores the need to study these problems in animal models in order to develop new and effective treatments. The foundation of our study is the fact that PTH has many symptoms of chronic migraine, including photosensitivity. We propose to evaluate facial measures of discomfort that accompany photosensitivity in a mouse model of mild TBI for an extended period of time (9 months) post-injury. Importantly, we will also test whether two new putative treatments for PTH are able to reverse these symptoms. We hypothesize that a facial response assay measuring eye squint, along with nose and cheek bulges, as pain indices will reliably measure photosensitivity and discomfort in a mouse model of PTH. For this we will also use a novel hyperosmolar eyedrop as an acute sensory pain challenge, which provides further correlation between human patients and our animal model. We further hypothesize that treatment with two complementary pharmacological agents will reduce and even reverse these symptoms when administered up to weeks after injury. The first agent to be tested is an antibody that inhibits the neuropeptide calcitonin gene-related peptide (CGRP). CGRP has been firmly established as a key player in migraine, and CGRP blocking antibodies have proven effective in early clinical trials as a preventative treatment for migraine, including chronic migraine. The improved toxicology profile of CGRP antibodies is especially encouraging for treating chronic PTH. The second class of agents to be tested is a neuroprotective compound developed by our lab, P7C3-S243. This compound is currently in Investigational New Drug-enabling studies for development of a new class of neuroprotective agents that have thus far shown great promise in multiple preclinical models of neurodegeneration, including TBI-associated cognitive, motor, and visual symptoms; amyotrophic lateral sclerosis; peripheral nerve degeneration; aging-associated cognitive decline; and Parkinson s disease. We thus propose to establish preclinical efficacy of two promising new therapeutics that act by different mechanisms. Specifically, P7C3-S243 boosts production of a key energy metabolite in cells, while the CGRP-directed agents most likely act by reducing neural activity in pain pathways. There is good rationale for testing these new agents for efficacy in prevention and treatment of PTH. Furthermore, we will be perfectly poised for studies of combination therapy, which might provide synergistically enhanced therapeutic effect. Taken together, our work will provide a basis for developing new ways to diagnose and improve treatment of military personnel with PTH.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610212
Entities
People
- Andrew Pieper
Organizations
- United States Army
- University of Iowa