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Scott Ferguson. 1 Roskamp Institute, Sarasota, Florida.
Benoit Mouzon. 1 Roskamp Institute, Sarasota, Florida.
Daniel Paris. 1 Roskamp Institute, Sarasota, Florida.
Destinee Aponte. 1 Roskamp Institute, Sarasota, Florida.
Laila Abdullah. 1 Roskamp Institute, Sarasota, Florida.
William Stewart. 2 Department of Neuropathology, Queen Elizabeth Glasgow University Hospital, Glasgow, United Kingdom. 3 Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, United Kingdom.
Michael Mullan. 1 Roskamp Institute, Sarasota, Florida. 4 Rock Creek Pharmaceuticals, Sarasota, Florida.
Fiona Crawford. 1 Roskamp Institute, Sarasota, Florida. 5 James A. Haley Veterans Hospital, Tampa, Florida.
Address correspondence to: Scott Ferguson, PhD, Roskamp Institute, 2040 Whitfield Avenue, Sarasota, FL 34243, E-mail: [email protected]
Introduction
In the United States traumatic brain injury (TBI) results in approximately 2.5 million emergency department visits per year, of which 75% are for mild TBI.1 Although these injuries are clinically classified as mild, exposure to repetitive injury is associated with chronic neurodegeneration and deficits that affect the long-term recovery and outcome of the patient.2 Although studies have shown that mild TBI can result in reduced productivity and impacts the quality of life of the patient, the pathophysiology driving these effects is unclear; hence strategies for therapeutic intervention have been slow to advance.3
TBI is a physical injury to the central nervous system (CNS) that can result in the initiation of downstream secondary injury mechanisms in the hours, days, and weeks following injury.4-7 After human TBI, neuropathology studies have shown evidence of inflammation and progressive white matter degeneration following just a single moderate or severe TBI,8 with imaging studies showing evidence of persistent neuroinflammation and reduced radial diffusivity and fractional anisotropy, even after mild injury.9-11 Consistent with these findings, animal studies have shown persistent inflammation and axonal damage in the corpus callosum of mice exposed to repetitive mild TBI (r-mTBI) at chronic time-points after injury,12,13 with white matter disruption and an increase in radial diffusivity 60 days after r-mTBI in rats.14
Pro-inflammatory genes and nuclear factor-kappa B cells (NF-κB) have been reported to remain activated for up to 1 year in a rat model of closed head injury (CHI).15,16 In mice, chronic microglial activation in combination with progressive lesion expansion has been seen after moderate cortical injury up to...