TY - JOUR
T1 - Early preclinical plasma protein biomarkers of brain trauma are influenced by early seizures and levetiracetam
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.
AU - for the EpiBioS4Rx Study Group
N1 - Funding Information:
The study was funded by the NINDS Center without Walls, U54 NS100064 (EpiBioS4Rx). Additional research support is listed below. WBM acknowledges grant support by NINDS U54 NS100064, NINDS R01 NS127524, and U.S. Department of Defense (W81XWH2210510, W81XWH2210210). JC was supported by NINDS/NIDDK U54 NS065768, NINDS NS100064, NIMH R01 MH107394, NICHD R21 HD101075, and a research grant from Pfizer. SRS was supported by a NHMRC Career Development Fellowship (#APP1159645). TJOB was supported by a NHMRC Investigator Grant (#APP1176426) and NINDS U54 NS100064, NINDS R01 NS127524. RJS was supported by R01 NS106957, NS127524, and U54 NS100064. SLM is the Charles Frost Chair in Neurosurgery and Neurology and acknowledges grant support by NIH U54 NS100064, NINDS R01 NS127524, and NS43209, U.S. Department of Defense (W81XWH‐18‐1‐0612, W81XWH‐22‐1‐0510, W81XWH‐22‐1‐0210), the Heffer Family and the Segal Family Foundations, and the Abbe Goldstein/Joshua Lurie and Laurie Marsh/Dan Levitz families. ASG acknowledges grant support by NINDS U54 NS100064, NINDS R01 NS127524, R01 NS091170, U.S. Department of Defense (W81XWH‐18‐1‐0612, W81XWH‐22‐1‐0510, W81XWH‐22‐1‐0210), American Epilepsy Society seed grant, the Heffer Family and the Segal Family Foundations, and the Abbe Goldstein/Joshua Lurie and Laurie Marsh/Dan Levitz families. We acknowledge the technical contribution of Dr Christos Lisgaras. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Funding Information:
WBM is on the editorial board of . JC received research support from Pfizer for a project unrelated to this study. TJO's institution has received funding and consultancy fees from Eisai, UCB, Biogen, Supernus, Praxis, ES Therapeutics, and Epiminder. SLM is serving as Associate Editor of . He is on the editorial board of , and . He receives from Elsevier for his work as Associate Editor in ; annual compensation from ; and royalties from 2 books he co‐edited. DVA is Associate Editor of , without compensation. ASG is the Editor‐in‐Chief of , associate editor of , and receives royalties from Elsevier (publications, journal editorial board participation), Medlink (publications), and Morgan and Claypool (publications). The other authors do not report conflicts of interests that relate to this study. Epilepsia Open Neurobiology of Disease Brain and Development Pediatric Neurology, Annals of Neurology, MedLink Physiological Research Neurobiology of Disease MedLink Frontiers in Neurology Epilepsia Open Neurobiology of Disease
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
UR - http://www.scopus.com/inward/record.url?scp=85153752045&partnerID=8YFLogxK
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 -