Citation

Mondello S, Shear DA, Bramlett HM, Dixon CE, Schmid Maj KE, Dietrich WD, Wang KK, Hayes RL, Glushakova O, Catania M, Richieri S, Povlishock J, Tortella FC, Kochanek PM. J. Neurotrauma 2015; 33(6): 595-605.

Affiliation

United States ; kochanekpm@ccm.upmc.edu.

Copyright

(Copyright © 2015, Mary Ann Liebert Publishers)

DOI

10.1089/neu.2015.4132

PMID

26671651

Abstract

Operation Brain Trauma Therapy (OBTT) is a multi-center pre-clinical drug screening consortium testing promising therapies for traumatic brain injury (TBI) in 3 well-established TBI models in rats, namely parasagittal fluid percussion injury (FPI), controlled cortical impact (CCI), and penetrating ballistic-like brain injury (PBBI). This manuscript 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 were subjected to CCI, FPI, or PBBI and treated with vehicle. 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 ELISA 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+vehicle 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 24-4h GFAP levels and neuropathological and behavioral outcomes. Circulating GFAP levels at 4 and 24 h were powerful predictors of 21 d 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 models, 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 endpoint.

Language: en