Operation Brain Trauma Therapy: An Exploratory Study of Levetiracetam Treatment Following Mild Traumatic Brain Injury in the Micro Pig

Abstract

Operation brain trauma therapy (OBTT) is a drug- and biomarker-screening consortium intended to improve the quality of preclinical studies and provide a rigorous framework to increase the translational potential of experimental traumatic brain injury (TBI) treatments. Levetiracetam (LEV) is an antiepileptic agent that was the fifth drug tested by OBTT in three independent rodent models of moderate to severe TBI. To date, LEV has been the most promising drug tested by OBTT and was therefore advanced to testing in the pig. Adult male micro pigs were subjected to a mild central fluid percussion brain injury followed by a post-injury intravenous infusion of either 170 mg/kg LEV or vehicle. Systemic physiology was assessed throughout the post-injury period. Serial serum samples were obtained pre-injury as well as at 1 min, 30 min, 1 h, 3 h, and 6 h post-injury for a detailed analysis of the astroglial biomarker glial fibrillary acidic protein (GFAP) and ubiquitin carboxy-terminal hydrolase L1. Tissue was collected 6 h following injury for histological assessment of diffuse axonal injury using antibodies against the amyloid precursor protein (APP). The animals showed significant increases in circulating GFAP levels from baseline to 6 h post-injury; however, LEV treatment was associated with greater GFAP increases compared to the vehicle. There were no differences in the numbers of APP+ axonal swellings within the pig thalamus with LEV treatment; however, significant alterations in the morphological properties of the APP+ axonal swellings, including reduced swelling area and increased swelling roundness, were observed. Additionally, expression of the neurite outgrowth marker, growth-associated protein 43, was reduced in axonal swellings following LEV treatment, suggesting potential effects on axonal outgrowth that warrant further investigation.

Early preclinical plasma protein biomarkers of brain trauma are influenced by early seizures and levetiracetam

“…However, the OBTT studies did not report potential interference of early seizures on the LEV effects upon the plasma biomarkers; our findings suggested rather that LEV inhibits the seizure‐induced increase in 2d‐UCHL1. We did not see any significant effect of LEV upon plasma GFAP levels, similar to a previous study in the central fluid percussion micro‐pig model of mild TBI 98 . However, LEV reduced serum GFAP levels within 24 hrs in the CCI and PBBI models 92 .…”

“…We did not see any significant effect of LEV upon plasma GFAP levels, similar to a previous study in the central fluid percussion micro-pig model of mild TBI. 98 However, LEV reduced serum GFAP levels within 24 hrs in the CCI and PBBI models. 92 Additionally, LEV has been reported to have anti-inflammatory or anti-oxidant effects, preventing blood brain barrier dysfunction, which may contribute to antiseizure effects.…”

Translating from mice to humans: using preclinical blood-based biomarkers for the prognosis and treatment of traumatic brain injury

“…Notably, when LEV was tested in a gyroencephalic FPI model (128) there were no changes in post-traumatic GFAP levels due to LEV treatment. Collectively, these data suggest that post-traumatic GFAP pharmacodynamic response may be model-dependent (59,128).…”

A Precision Medicine Agenda in Traumatic Brain Injury

“… a. Operation Brain Trauma Therapy ( Lafrenaye et al, 2020 ) b. TBI Models Systems (TBIMS) ( NDSC, 2016 ) c. Common Data Elements (CDE) ( NINDS, 2017 ) d. Transforming Research and Clinical Knowledge in TBI (TRACK TBI) ( TRACK-TBI, 2014 ) e. TRACK-TBI Precision Medicine ( UCSF, 2018 ) f. TBI Endpoints Development (TED) ( UCSF, 2014 ) g. Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) ( Maas et al, 2015 ) h. Concussion Assessment, Research and Education (CARE) Consortium ( CARE Consortium, 2022 ) …”