Serum-Based Phospho-Neurofilament-Heavy Protein as Theranostic Biomarker in Three Models of Traumatic Brain Injury: An Operation Brain Trauma Therapy Study

Zhihui Yang, Tian Zhu, Stefania Mondello, Miis Akel, Aaron T. Wong, Isha M. Kothari, Fan Lin, Deborah A. Shear, Janice S. Gilsdorf, Lai Yee Leung, Helen M. Bramlett, C. Edward Dixon, W. Dalton Dietrich, Ronald L. Hayes, John T. Povlishock, Frank C. Tortella, Patrick M. Kochanek, Kevin K.W. Wang

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1), markers of glial and neuronal cell body injury, respectively, have been previously selected by the Operation Brain Trauma Therapy (OBTT) pre-clinical therapy and biomarker screening consortium as drug development tools. However, traumatic axonal injury (TAI) also represents a major consequence and determinant of adverse outcomes after traumatic brain injury (TBI). Thus, biomarkers capable of assessing TAI are much needed. Neurofilaments (NFs) are found exclusively in axons. Here, we evaluated phospho-neurofilament-H (pNF-H) protein as a possible new TAI marker in serum and cerebrospinal fluid (CSF) across three rat TBI models in studies carried out by the OBTT consortium, namely, controlled cortical impact (CCI), parasagittal fluid percussion (FPI), and penetrating ballistics-like brain injury (PBBI). We indeed found that CSF and serum pNF-H levels are robustly elevated by 24 h post-injury in all three models. Further, in previous studies by OBTT, levetiracetam showed the most promising benefits, whereas nicotinamide showed limited benefit only at high dose (500 mg/kg). Thus, serum samples from the same repository collected by OBTT were evaluated. Treatment with 54 mg/kg intravenously of levetiracetam in the CCI model and 170 mg/kg in the PBBI model significantly attenuated pNF-H levels at 24 h post-injury as compared to respective vehicle groups. In contrast, nicotinamide (50 or 500 mg/kg) showed no reduction of pNF-H levels in CCI or PBBI models. Our current study suggests that pNF-H is a useful theranostic blood-based biomarker for TAI across different rodent TBI models. In addition, our data support levetiracetam as the most promising TBI drug candidate screened by OBTT to date.

Original languageEnglish
Pages (from-to)348-359
Number of pages12
JournalJournal of Neurotrauma
Volume36
Issue number2
DOIs
Publication statusPublished - Jan 15 2019

Fingerprint

Neurofilament Proteins
etiracetam
Biomarkers
Intermediate Filaments
Serum
Wounds and Injuries
Brain Injuries
Therapeutics
Niacinamide
Cerebrospinal Fluid
Ubiquitin Thiolesterase
Percussion
Traumatic Brain Injury
Theranostic Nanomedicine
Glial Fibrillary Acidic Protein
Protein C
Neuroglia
Pharmaceutical Preparations
Axons
Rodentia

Keywords

  • biomarker
  • controlled cortical impact
  • fluid percussion
  • levetiracetam
  • nicotinamide
  • penetrating ballistic-like brain injury
  • pNF-H

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Serum-Based Phospho-Neurofilament-Heavy Protein as Theranostic Biomarker in Three Models of Traumatic Brain Injury : An Operation Brain Trauma Therapy Study. / Yang, Zhihui; Zhu, Tian; Mondello, Stefania; Akel, Miis; Wong, Aaron T.; Kothari, Isha M.; Lin, Fan; Shear, Deborah A.; Gilsdorf, Janice S.; Leung, Lai Yee; Bramlett, Helen M.; Dixon, C. Edward; Dietrich, W. Dalton; Hayes, Ronald L.; Povlishock, John T.; Tortella, Frank C.; Kochanek, Patrick M.; Wang, Kevin K.W.

In: Journal of Neurotrauma, Vol. 36, No. 2, 15.01.2019, p. 348-359.

Research output: Contribution to journalArticle

Yang, Z, Zhu, T, Mondello, S, Akel, M, Wong, AT, Kothari, IM, Lin, F, Shear, DA, Gilsdorf, JS, Leung, LY, Bramlett, HM, Dixon, CE, Dietrich, WD, Hayes, RL, Povlishock, JT, Tortella, FC, Kochanek, PM & Wang, KKW 2019, 'Serum-Based Phospho-Neurofilament-Heavy Protein as Theranostic Biomarker in Three Models of Traumatic Brain Injury: An Operation Brain Trauma Therapy Study', Journal of Neurotrauma, vol. 36, no. 2, pp. 348-359. https://doi.org/10.1089/neu.2017.5586
Yang, Zhihui ; Zhu, Tian ; Mondello, Stefania ; Akel, Miis ; Wong, Aaron T. ; Kothari, Isha M. ; Lin, Fan ; Shear, Deborah A. ; Gilsdorf, Janice S. ; Leung, Lai Yee ; Bramlett, Helen M. ; Dixon, C. Edward ; Dietrich, W. Dalton ; Hayes, Ronald L. ; Povlishock, John T. ; Tortella, Frank C. ; Kochanek, Patrick M. ; Wang, Kevin K.W. / Serum-Based Phospho-Neurofilament-Heavy Protein as Theranostic Biomarker in Three Models of Traumatic Brain Injury : An Operation Brain Trauma Therapy Study. In: Journal of Neurotrauma. 2019 ; Vol. 36, No. 2. pp. 348-359.
@article{17378923762e43d9bd997e658502d10a,
title = "Serum-Based Phospho-Neurofilament-Heavy Protein as Theranostic Biomarker in Three Models of Traumatic Brain Injury: An Operation Brain Trauma Therapy Study",
abstract = "Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1), markers of glial and neuronal cell body injury, respectively, have been previously selected by the Operation Brain Trauma Therapy (OBTT) pre-clinical therapy and biomarker screening consortium as drug development tools. However, traumatic axonal injury (TAI) also represents a major consequence and determinant of adverse outcomes after traumatic brain injury (TBI). Thus, biomarkers capable of assessing TAI are much needed. Neurofilaments (NFs) are found exclusively in axons. Here, we evaluated phospho-neurofilament-H (pNF-H) protein as a possible new TAI marker in serum and cerebrospinal fluid (CSF) across three rat TBI models in studies carried out by the OBTT consortium, namely, controlled cortical impact (CCI), parasagittal fluid percussion (FPI), and penetrating ballistics-like brain injury (PBBI). We indeed found that CSF and serum pNF-H levels are robustly elevated by 24 h post-injury in all three models. Further, in previous studies by OBTT, levetiracetam showed the most promising benefits, whereas nicotinamide showed limited benefit only at high dose (500 mg/kg). Thus, serum samples from the same repository collected by OBTT were evaluated. Treatment with 54 mg/kg intravenously of levetiracetam in the CCI model and 170 mg/kg in the PBBI model significantly attenuated pNF-H levels at 24 h post-injury as compared to respective vehicle groups. In contrast, nicotinamide (50 or 500 mg/kg) showed no reduction of pNF-H levels in CCI or PBBI models. Our current study suggests that pNF-H is a useful theranostic blood-based biomarker for TAI across different rodent TBI models. In addition, our data support levetiracetam as the most promising TBI drug candidate screened by OBTT to date.",
keywords = "biomarker, controlled cortical impact, fluid percussion, levetiracetam, nicotinamide, penetrating ballistic-like brain injury, pNF-H",
author = "Zhihui Yang and Tian Zhu and Stefania Mondello and Miis Akel and Wong, {Aaron T.} and Kothari, {Isha M.} and Fan Lin and Shear, {Deborah A.} and Gilsdorf, {Janice S.} and Leung, {Lai Yee} and Bramlett, {Helen M.} and Dixon, {C. Edward} and Dietrich, {W. Dalton} and Hayes, {Ronald L.} and Povlishock, {John T.} and Tortella, {Frank C.} and Kochanek, {Patrick M.} and Wang, {Kevin K.W.}",
year = "2019",
month = "1",
day = "15",
doi = "10.1089/neu.2017.5586",
language = "English",
volume = "36",
pages = "348--359",
journal = "Journal of Neurotrauma",
issn = "0897-7151",
publisher = "Mary Ann Liebert Inc.",
number = "2",

}

TY - JOUR

T1 - Serum-Based Phospho-Neurofilament-Heavy Protein as Theranostic Biomarker in Three Models of Traumatic Brain Injury

T2 - An Operation Brain Trauma Therapy Study

AU - Yang, Zhihui

AU - Zhu, Tian

AU - Mondello, Stefania

AU - Akel, Miis

AU - Wong, Aaron T.

AU - Kothari, Isha M.

AU - Lin, Fan

AU - Shear, Deborah A.

AU - Gilsdorf, Janice S.

AU - Leung, Lai Yee

AU - Bramlett, Helen M.

AU - Dixon, C. Edward

AU - Dietrich, W. Dalton

AU - Hayes, Ronald L.

AU - Povlishock, John T.

AU - Tortella, Frank C.

AU - Kochanek, Patrick M.

AU - Wang, Kevin K.W.

PY - 2019/1/15

Y1 - 2019/1/15

N2 - Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1), markers of glial and neuronal cell body injury, respectively, have been previously selected by the Operation Brain Trauma Therapy (OBTT) pre-clinical therapy and biomarker screening consortium as drug development tools. However, traumatic axonal injury (TAI) also represents a major consequence and determinant of adverse outcomes after traumatic brain injury (TBI). Thus, biomarkers capable of assessing TAI are much needed. Neurofilaments (NFs) are found exclusively in axons. Here, we evaluated phospho-neurofilament-H (pNF-H) protein as a possible new TAI marker in serum and cerebrospinal fluid (CSF) across three rat TBI models in studies carried out by the OBTT consortium, namely, controlled cortical impact (CCI), parasagittal fluid percussion (FPI), and penetrating ballistics-like brain injury (PBBI). We indeed found that CSF and serum pNF-H levels are robustly elevated by 24 h post-injury in all three models. Further, in previous studies by OBTT, levetiracetam showed the most promising benefits, whereas nicotinamide showed limited benefit only at high dose (500 mg/kg). Thus, serum samples from the same repository collected by OBTT were evaluated. Treatment with 54 mg/kg intravenously of levetiracetam in the CCI model and 170 mg/kg in the PBBI model significantly attenuated pNF-H levels at 24 h post-injury as compared to respective vehicle groups. In contrast, nicotinamide (50 or 500 mg/kg) showed no reduction of pNF-H levels in CCI or PBBI models. Our current study suggests that pNF-H is a useful theranostic blood-based biomarker for TAI across different rodent TBI models. In addition, our data support levetiracetam as the most promising TBI drug candidate screened by OBTT to date.

AB - Glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1), markers of glial and neuronal cell body injury, respectively, have been previously selected by the Operation Brain Trauma Therapy (OBTT) pre-clinical therapy and biomarker screening consortium as drug development tools. However, traumatic axonal injury (TAI) also represents a major consequence and determinant of adverse outcomes after traumatic brain injury (TBI). Thus, biomarkers capable of assessing TAI are much needed. Neurofilaments (NFs) are found exclusively in axons. Here, we evaluated phospho-neurofilament-H (pNF-H) protein as a possible new TAI marker in serum and cerebrospinal fluid (CSF) across three rat TBI models in studies carried out by the OBTT consortium, namely, controlled cortical impact (CCI), parasagittal fluid percussion (FPI), and penetrating ballistics-like brain injury (PBBI). We indeed found that CSF and serum pNF-H levels are robustly elevated by 24 h post-injury in all three models. Further, in previous studies by OBTT, levetiracetam showed the most promising benefits, whereas nicotinamide showed limited benefit only at high dose (500 mg/kg). Thus, serum samples from the same repository collected by OBTT were evaluated. Treatment with 54 mg/kg intravenously of levetiracetam in the CCI model and 170 mg/kg in the PBBI model significantly attenuated pNF-H levels at 24 h post-injury as compared to respective vehicle groups. In contrast, nicotinamide (50 or 500 mg/kg) showed no reduction of pNF-H levels in CCI or PBBI models. Our current study suggests that pNF-H is a useful theranostic blood-based biomarker for TAI across different rodent TBI models. In addition, our data support levetiracetam as the most promising TBI drug candidate screened by OBTT to date.

KW - biomarker

KW - controlled cortical impact

KW - fluid percussion

KW - levetiracetam

KW - nicotinamide

KW - penetrating ballistic-like brain injury

KW - pNF-H

UR - http://www.scopus.com/inward/record.url?scp=85054932033&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054932033&partnerID=8YFLogxK

U2 - 10.1089/neu.2017.5586

DO - 10.1089/neu.2017.5586

M3 - Article

C2 - 29987972

AN - SCOPUS:85054932033

VL - 36

SP - 348

EP - 359

JO - Journal of Neurotrauma

JF - Journal of Neurotrauma

SN - 0897-7151

IS - 2

ER -