Neuropeptide Modulation of Cerebral Blood Flow to Improve Neurological and Psychological Outcomes Following TBI in the Presence and Absence of Traumatic Stress
Abstract
Peer Reviewed Medical Research Program (PRMRP) Fiscal Year 2022 (FY22) Topic Area to be addressed: This proposal addresses the Neuroscience Topic Area of Trauma and is directed toward two strategic goals: (1) Foundational Studies and (2) Prevention. Foundationally, this project will examine a neuropeptide as a mechanism by which blood flow in the brain is immediately compromised following traumatic brain injury (TBI), with posttraumatic stress disorder (PTSD) and the combination of TBI+PTSD, such that brain tissue in the impact area, or in several brain regions with PTSD, function poorly due to the drop in oxygen levels (ischemia) that may stay reduced for many days. We will test our hypothesis that increased levels of the neuropeptide are responsible for reduced blood flow and subsequent problems with balance and coordinated movement, anxiety, pain, and memory loss, by treating with one of two different drugs that reduce the actions of the neuropeptide. Treatment will begin shortly after the TBI or traumatic stressor with the goal to prevent brain blood flow reduction and prevent or reduce appearance and severity of symptoms over the next 2 weeks. 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 United States. TBI ranges in severity from mild, moderate 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, the symptoms DO worsen, 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 treatments for TBI approved by the U.S. Food and Drug Administration (FDA) that could be given after the injury that would prevent or reduce the severity of injury related problems. There is compelling data from four different brain injury models to suggest that levels of a natural substance in the brain (the neuropeptide Nociceptin/Orphanin FQ or N/OFQ) increase after TBI and stay 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 (called the N/OFQ peptide (NOP) receptor), 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 improve symptoms of pain and anxiety in a model of PTSD. Objectives: We will use a rat model of TBI that produces mild and moderate TBI with physical symptoms related to injury severity (impaired balance and poor learning and memory, pain, and anxiety-like behaviors), that allows us to directly measure blood flow on injured and uninjured sides of the brain, and that easily can be combined with a model of PTSD. Our objectives are (1) to measure brain blood flow immediately after moderate TBI, PTSD or TBI/PTSD and then measure the ability of a new drug to reverse the injury-induced drop in blood flow; (2) Use a novel PET imaging agent to visualize areas of reduced blood flow throughout the brain over 8 days to compare the development of ischemia with the different types and combinations of trauma
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310517
Entities
People
- Kelly Standifer
Organizations
- United States Army
- University of Oklahoma Health Sciences Center