Traumatic brain injury (TBI) is the leading cause of death in children and is one of the major causes of disability in all ages. Brain damage resulting from a TBI is very complex in that the primary injury initiates a chain of events that expands spatially and temporally beyond the initial injury and leads to additional neurological damage (secondary injury) and possibly death. Although it is well understood that early intervention is necessary to prevent or attenuate the chain of events leading to secondary injury following TBI, there is yet no standard effective treatment for TBI. Recent studies by the PI and her collaborators indicate that a single dose of MK-886, the first identified inhibitor of 5-lipoxygenae activating protein (FLAP), given before or after fluid percussion injury (FPI) blocks leukotriene production and significantly attenuates edema, cell death, and subsequent motor and cognitive deficits. These findings indicate that: Cellular damage at the time of TBI results in the early activation (within minutes) of the 5-lipoxygenase inflammatory pathway resulting in the generation of leukotrienes that, in turn, signal adverse effects leading to secondary brain injury. Administration of a FLAP inhibitor blocks this process and thus may be effective at preventing or attenuating secondary brain injury associated with TBI. This revised R-21 research program will focus on the translational potential of FLAP inhibition for TBI.
The specific aims of this proposal are to: #1: Examine brain bioavailability and efficacy of MK-591, a 2nd generation FLAP inhibitor that has greater potency, selectivity, and longer half-life than MK-886, in blocking TBI-induced leukotriene production. #2: Establish the therapeutic window for MK-591 pharmacological blockade of TBI-related outcomes. The results from this study will provide preliminary data on brain bioavailability of MK-591 and will elucidate the therapeutic potential of specifically blockig FLAP-mediated leukotriene production in the brain in TBI.

Public Health Relevance

Brain damage resulting from a traumatic brain injury (TBI) is complex in that the primary injury initiates a chain of events that expand beyond the initial site f injury and lead to additional neurological damage (secondary injury) and possibly death. Although it is well understood that early intervention is necessary to prevent or interrupt the chain of events that lead to secondary injury following TBI, there is yet no effective treatment fo TBI. This R21 proposal explores the use of 5-lipoxygenase activating protein (FLAP) inhibitors, drugs that block the production of pro-inflammatory leukotrienes, as a means of blocking secondary injury after TBI.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS079435-02
Application #
8660720
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Bellgowan, Patrick S F
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Aurora
State
CO
Country
United States
Zip Code
80045
Corser-Jensen, Chelsea E; Goodell, Dayton J; Freund, Ronald K et al. (2014) Blocking leukotriene synthesis attenuates the pathophysiology of traumatic brain injury and associated cognitive deficits. Exp Neurol 256:7-16