TY - JOUR
T1 - Early preclinical plasma protein biomarkers of brain trauma are influenced by early seizures and levetiracetam
AU - For the EpiBioS4Rx Study Group
AU - Saletti, Patricia G.
AU - Mowrey, Wenzhu B.
AU - Liu, Wei
AU - Li, Qianyun
AU - McCullough, Jesse
AU - Aniceto, Roxanne
AU - Lin, I. Hsuan
AU - Eklund, Michael
AU - Casillas-Espinosa, Pablo M.
AU - Ali, Idrish
AU - Santana-Gomez, Cesar
AU - Coles, Lisa
AU - Shultz, Sandy R.
AU - Jones, Nigel
AU - Staba, Richard
AU - O'Brien, Terence J.
AU - Moshé, Solomon L.
AU - Agoston, Denes V.
AU - Galanopoulou, Aristea S.
N1 - Publisher Copyright:
© 2023 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
PY - 2023/6
Y1 - 2023/6
N2 - Objective: We used the lateral fluid percussion injury (LFPI) model of moderate-to-severe traumatic brain injury (TBI) to identify early plasma biomarkers predicting injury, early post-traumatic seizures or neuromotor functional recovery (neuroscores), considering the effect of levetiracetam, which is commonly given after severe TBI. Methods: Adult male Sprague–Dawley rats underwent left parietal LFPI, received levetiracetam (200 mg/kg bolus, 200 mg/kg/day subcutaneously for 7 days [7d]) or vehicle post-LFPI, and were continuously video-EEG recorded (n = 14/group). Sham (craniotomy only, n = 6), and naïve controls (n = 10) were also used. Neuroscores and plasma collection were done at 2d or 7d post-LFPI or equivalent timepoints in sham/naïve. Plasma protein biomarker levels were determined by reverse phase protein microarray and classified according to injury severity (LFPI vs. sham/control), levetiracetam treatment, early seizures, and 2d-to-7d neuroscore recovery, using machine learning. Results: Low 2d plasma levels of Thr231-phosphorylated tau protein (pTAU-Thr231) and S100B combined (ROC AUC = 0.7790) predicted prior craniotomy surgery (diagnostic biomarker). Levetiracetam-treated LFPI rats were differentiated from vehicle treated by the 2d-HMGB1, 2d-pTAU-Thr231, and 2d-UCHL1 plasma levels combined (ROC AUC = 0.9394) (pharmacodynamic biomarker). Levetiracetam prevented the seizure effects on two biomarkers that predicted early seizures only among vehicle-treated LFPI rats: pTAU-Thr231 (ROC AUC = 1) and UCHL1 (ROC AUC = 0.8333) (prognostic biomarker of early seizures among vehicle-treated LFPI rats). Levetiracetam-resistant early seizures were predicted by high 2d-IFNγ plasma levels (ROC AUC = 0.8750) (response biomarker). 2d-to-7d neuroscore recovery was best predicted by higher 2d-S100B, lower 2d-HMGB1, and 2d-to-7d increase in HMGB1 or decrease in TNF (P < 0.05) (prognostic biomarkers). Significance: Antiseizure medications and early seizures need to be considered in the interpretation of early post-traumatic biomarkers.
AB - Objective: We used the lateral fluid percussion injury (LFPI) model of moderate-to-severe traumatic brain injury (TBI) to identify early plasma biomarkers predicting injury, early post-traumatic seizures or neuromotor functional recovery (neuroscores), considering the effect of levetiracetam, which is commonly given after severe TBI. Methods: Adult male Sprague–Dawley rats underwent left parietal LFPI, received levetiracetam (200 mg/kg bolus, 200 mg/kg/day subcutaneously for 7 days [7d]) or vehicle post-LFPI, and were continuously video-EEG recorded (n = 14/group). Sham (craniotomy only, n = 6), and naïve controls (n = 10) were also used. Neuroscores and plasma collection were done at 2d or 7d post-LFPI or equivalent timepoints in sham/naïve. Plasma protein biomarker levels were determined by reverse phase protein microarray and classified according to injury severity (LFPI vs. sham/control), levetiracetam treatment, early seizures, and 2d-to-7d neuroscore recovery, using machine learning. Results: Low 2d plasma levels of Thr231-phosphorylated tau protein (pTAU-Thr231) and S100B combined (ROC AUC = 0.7790) predicted prior craniotomy surgery (diagnostic biomarker). Levetiracetam-treated LFPI rats were differentiated from vehicle treated by the 2d-HMGB1, 2d-pTAU-Thr231, and 2d-UCHL1 plasma levels combined (ROC AUC = 0.9394) (pharmacodynamic biomarker). Levetiracetam prevented the seizure effects on two biomarkers that predicted early seizures only among vehicle-treated LFPI rats: pTAU-Thr231 (ROC AUC = 1) and UCHL1 (ROC AUC = 0.8333) (prognostic biomarker of early seizures among vehicle-treated LFPI rats). Levetiracetam-resistant early seizures were predicted by high 2d-IFNγ plasma levels (ROC AUC = 0.8750) (response biomarker). 2d-to-7d neuroscore recovery was best predicted by higher 2d-S100B, lower 2d-HMGB1, and 2d-to-7d increase in HMGB1 or decrease in TNF (P < 0.05) (prognostic biomarkers). Significance: Antiseizure medications and early seizures need to be considered in the interpretation of early post-traumatic biomarkers.
KW - inflammation
KW - lateral fluid percussion injury
KW - levetiracetam
KW - neuromotor recovery
KW - tau
KW - traumatic brain injury
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U2 - 10.1002/epi4.12738
DO - 10.1002/epi4.12738
M3 - Article
C2 - 37026764
AN - SCOPUS:85153752045
SN - 2470-9239
VL - 8
SP - 586
EP - 608
JO - Epilepsia Open
JF - Epilepsia Open
IS - 2
ER -