Operation
Brain Trauma Therapy (OBTT) is a multicenter pre-clinical drug screening consortium testing promising
therapies for
traumatic brain injury (TBI) in three well-established models of TBI in rats--namely, parasagittal fluid percussion injury (FPI), controlled cortical impact (CCI), and penetrating ballistic-like
brain injury (PBBI). This article presents unique characterization of these models using histological and behavioral outcomes and novel candidate
biomarkers from the first three treatment trials of OBTT. Adult rats underwent CCI, FPI, or PBBI and were treated with vehicle (VEH). Shams underwent all manipulations except
trauma. The glial marker
glial fibrillary acidic protein (GFAP) and the neuronal marker
ubiquitin C-terminal hydrolase (UCH-L1) were measured by
enzyme-linked
immunosorbent assay in blood at 4 and 24 h, and their delta 24-4 h was calculated for each marker. Comparing
sham groups across experiments, no differences were found in the same model. Similarly, comparing TBI + VEH groups across experiments, no differences were found in the same model. GFAP was acutely increased in injured rats in each model, with significant differences in levels and temporal patterns mirrored by significant differences in delta 24-4 h GFAP levels and neuropathological and behavioral outcomes. Circulating GFAP levels at 4 and 24 h were powerful predictors of 21 day
contusion volume and tissue loss. UCH-L1 showed similar tendencies, albeit with less robust differences between
sham and injury groups. Significant differences were also found comparing shams across the models. Our findings (1) demonstrate that TBI models display specific
biomarker profiles, functional deficits, and pathological consequence; (2) support the concept that there are different cellular, molecular, and pathophysiological responses to TBI in each model; and (3) advance our understanding of TBI, providing opportunities for a successful translation and holding promise for
theranostic applications. Based on our findings, additional studies in pre-clinical models should pursue assessment of GFAP as a surrogate histological and/or
theranostic end-point.