NOP Receptor Modulator Treatment Optimizes Cognitive, Locomotor, and Sensory Outcomes of Mild Concussive TBI with and Without PTSD
Abstract
Background: This proposal addresses three different focus areas (Understand, Prevent and Assess, and Treat). We seek to understand how exposure to traumatic stress prior to mild concussive TBI alters the appearance and severity of TBI and its outcomes; assess whether early detection of brain hypoxia with a novel non-invasive imaging agent predicts the severity of those outcomes; and treat within 12 hours and daily for 7 days with a novel drug to prevent and/or reduce severity of sensory, locomotor and cognitive dysfunction and anxiety-like behaviors after TBI or TBI+PTSD in males and females. Rationale: TBI and PTSD are major causes of disability for military personnel and Veterans as well as civilians. TBI is the leading cause of death and disability in young adults (<40 years old) in the U.S. TBI ranges in severity from mild to severe. In the military over the last 21 years, 80% of TBIs were mild. Mild TBIs are most common in civilians as well and often go unreported. When patients do seek medical advice, they are checked for skull fractures and bleeding; if there is none, they are sent home to follow up if needed if initial symptoms of headache, dizziness, imbalance, loss of memory, inability to focus, or increased sensitivity to light worsen. In ~15% of patients with TBI, symptoms DO get worse or persist for months to years. Complications from TBI are made worse if the patient has PTSD; estimates are that one-third of military Veterans with TBI also have PTSD. Individuals with TBI are more likely to develop PTSD and vice versa. Impaired motor function, pain, anxiety, and memory loss are significant problems for those with TBI or TBI/PTSD. However, there are no FDA-approved treatments for TBI. Development of treatments that could be given after the injury that would prevent or reduce the severity of injury and injury- related problems are an important unmet need. There are compelling data from four different brain injury models to suggest that levels of a natural substance in the brain increases after TBI and stays elevated for at least 8 days. This substance reduces blood flow in the brain that further damages brain cells and their ability to talk with each other properly. When actions of this substance are reduced by blocking its ability to bind to its receptor site, blood flow within the brain increases, and TBI-induced problems with balance, motor coordination, and pain are resolved or improved. In addition, blockade of the actions of this substance also improves symptoms of pain and anxiety in a model of PTSD. Objectives: We will use a rat model of TBI that generates the most common type of TBI (mild TBI with no skull fracture or obvious damage). It produces physical symptoms related to injury severity (impaired balance, poor learning and memory, and anxiety-like behaviors) and can be combined with a model of PTSD. Our objectives are (1) to use a novel PET imaging agent to visualize reduced blood flow within the first 5 days following impact and to correlate that with increased brain peptide and decreased neurological function and (2) to test a novel drug for its ability to prevent or reduce the lack of blood flow that occurs early after injury as well as the symptoms produced by the TBI or TBI+ PTSD in male and female rats over a 30-day period. Our study is specifically designed to test for differences in symptoms and drug response in males and females, because females may present with different types and severity of symptoms than males and are often not included in initial drug development studies. We also will study, for the first time, how the severity of TBI symptoms is altered in rats that were subjected to both TBI and PTSD. Outcomes: There are no FDA-approved treatments for TBI, and only two FDA-approved treatments for PTSD. We propose a new treatment for patients with TBI or TBI+PTSD that may be administered shortly after any type of TBI to prevent disrupted blood flow to th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310340
Entities
People
- Kelly Standifer
Organizations
- United States Army
- University of Oklahoma Health Sciences Center