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

2021 ◽  
Vol 11 ◽  
Author(s):  
Audrey Lafrenaye ◽  
Stefania Mondello ◽  
John Povlishock ◽  
Karen Gorse ◽  
Susan Walker ◽  
...  

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.

2016 ◽  
Vol 33 (6) ◽  
pp. 581-594 ◽  
Author(s):  
Megan Browning ◽  
Deborah A. Shear ◽  
Helen M. Bramlett ◽  
C. Edward Dixon ◽  
Stefania Mondello ◽  
...  

2019 ◽  
Vol 36 (2) ◽  
pp. 348-359 ◽  
Author(s):  
Zhihui Yang ◽  
Tian Zhu ◽  
Stefania Mondello ◽  
Miis Akel ◽  
Aaron T. Wong ◽  
...  

2018 ◽  
Vol 89 (10) ◽  
pp. A42.1-A42
Author(s):  
Graham Neil SN ◽  
Jolly Amy E ◽  
Bourke Niall J ◽  
Scott Gregory ◽  
Cole James H ◽  
...  

BackgroundDementia rates are elevated after traumatic brain injury (TBI) and a subgroup develops chronic traumatic encephalopathy. Post-traumatic neurodegeneration can be measured by brain atrophy rates derived from neuroimaging, but it is unclear how atrophy relates to the initial pattern of injury.ObjectivesTo investigate the relationship between baseline TBI patterns and subsequent neurodegeneration measured by progressive brain atrophy.Methods55 patients after moderate-severe TBI (mean 3 years post-injury) and 20 controls underwent longitudinal MRI. Brain atrophy was quantified using the Jacobian determinant defined from volumetric T1 scans approximately one year apart. Diffuse axonal injury was measured using diffusion tensor imaging and focal injuries defined from T1 and FLAIR. Neuropsychological assessment was performed.ResultsAbnormal progressive brain atrophy was seen after TBI (~1.8%/year in white matter). This was accompanied by widespread reductions in fractional anisotropy, in keeping with the presence of diffuse axonal injury. There was a strong negative correlation between FA and brain atrophy, whereby areas of greater white matter damage showed greater atrophy over time.ConclusionsThe results show a strong relationship between the location of diffuse axonal injury and subsequent neurodegeneration. This suggests that TBI triggers progressive neurodegeneration through the long-lasting effects of diffuse axonal injury.


2016 ◽  
Vol 33 (6) ◽  
pp. 567-580 ◽  
Author(s):  
Andrea Mountney ◽  
Helen M. Bramlett ◽  
C. Edward Dixon ◽  
Stefania Mondello ◽  
W. Dalton Dietrich ◽  
...  

2018 ◽  
Vol 9 ◽  
Author(s):  
Patrick M. Kochanek ◽  
C. Edward Dixon ◽  
Stefania Mondello ◽  
Kevin K. K. Wang ◽  
Audrey Lafrenaye ◽  
...  

2021 ◽  
Author(s):  
Nicole Osier ◽  
Helen M. Bramlett ◽  
Deborah A. Shear ◽  
Stefania Mondello ◽  
Shaun W. Carlson ◽  
...  

2020 ◽  
Author(s):  
Ruchira M. Jha ◽  
Stefania Mondello ◽  
Helen M. Bramlett ◽  
C. Edward Dixon ◽  
Deborah A. Shear ◽  
...  

2016 ◽  
Vol 33 (6) ◽  
pp. 553-566 ◽  
Author(s):  
C. Edward Dixon ◽  
Helen M. Bramlett ◽  
W. Dalton Dietrich ◽  
Deborah A. Shear ◽  
Hong Q. Yan ◽  
...  

2016 ◽  
Vol 33 (6) ◽  
pp. 595-605 ◽  
Author(s):  
Stefania Mondello ◽  
Deborah A. Shear ◽  
Helen M. Bramlett ◽  
C. Edward Dixon ◽  
Kara E. Schmid ◽  
...  

2021 ◽  
Vol 22 (22) ◽  
pp. 12211
Author(s):  
Tamara Janković ◽  
Petra Dolenec ◽  
Jelena Rajič Bumber ◽  
Nika Gržeta ◽  
Jasna Kriz ◽  
...  

Traumatic brain injury (TBI) is a disabling disorder and a major cause of death and disability in the world. Both single and repetitive traumas affect the brain acutely but can also lead to chronic neurodegenerative changes. Clinical studies have shown some dissimilarities in transactive response DNA binding protein 43 (TDP-43) expression patterns following single versus repetitive TBI. We explored the acute cortical post-traumatic changes of TDP-43 using the lateral fluid percussion injury (LFPI) model of single moderate TBI in adult male mice and investigated the association of TDP-43 with post-traumatic neuroinflammation and synaptic plasticity. In the ipsilateral cortices of animals following LFPI, we found changes in the cytoplasmic and nuclear levels of TDP-43 and the decreased expression of postsynaptic protein 95 within the first 3 d post-injury. Subacute pathological changes of TDP-43 in the hippocampi of animals following LFPI and in mice exposed to repetitive mild TBI (rmTBI) were studied. Changes in the hippocampal TDP-43 expression patterns at 14 d following different brain trauma procedures showed pathological alterations only after single moderate, but not following rmTBI. Hippocampal LFPI-induced TDP-43 pathology was not accompanied by the microglial reaction, contrary to the findings after rmTBI, suggesting that different types of brain trauma may cause diverse pathophysiological changes in the brain, specifically related to the TDP-43 protein as well as to the microglial reaction. Taken together, our findings may contribute to a better understanding of the pathophysiological events following brain trauma.


Sign in / Sign up

Export Citation Format

Share Document