Screening of biochemical and molecular mechanisms of secondary injury and repair in the brain after experimental blast-induced traumatic brain injury in rats

Patrick M. Kochanek, C. Edward Dixon, David K. Shellington, Samuel S. Shin, Hülya Bayir, Edwin K. Jackson, Valerian E. Kagan, Hong Q. Yan, Peter V. Swauger, Steven A. Parks, David V. Ritzel, Richard Bauman, Robert S.B. Clark, Robert H. Garman, Faris Bandak, Geoffrey Ling, Larry W. Jenkins

Research output: Contribution to journalArticle

Abstract

Explosive blast-induced traumatic brain injury (TBI) is the signature insult in modern combat casualty care and has been linked to post-traumatic stress disorder, memory loss, and chronic traumatic encephalopathy. In this article we report on blast-induced mild TBI (mTBI) characterized by fiber-tract degeneration and axonal injury revealed by cupric silver staining in adult male rats after head-only exposure to 35 psi in a helium-driven shock tube with head restraint. We now explore pathways of secondary injury and repair using biochemical/molecular strategies. Injury produced ∼25% mortality from apnea. Shams received identical anesthesia exposure. Rats were sacrificed at 2 or 24 h, and brain was sampled in the hippocampus and prefrontal cortex. Hippocampal samples were used to assess gene array (RatRef-12 Expression BeadChip; Illumina, Inc., San Diego, CA) and oxidative stress (OS; ascorbate, glutathione, low-molecular-weight thiols [LMWT], protein thiols, and 4-hydroxynonenal [HNE]). Cortical samples were used to assess neuroinflammation (cytokines, chemokines, and growth factors; Luminex Corporation, Austin, TX) and purines (adenosine triphosphate [ATP], adenosine diphosphate, adenosine, inosine, 2′-AMP [adenosine monophosphate], and 5′-AMP). Gene array revealed marked increases in astrocyte and neuroinflammatory markers at 24 h (glial fibrillary acidic protein, vimentin, and complement component 1) with expression patterns bioinformatically consistent with those noted in Alzheimer's disease and long-term potentiation. Ascorbate, LMWT, and protein thiols were reduced at 2 and 24 h; by 24 h, HNE was increased. At 2 h, multiple cytokines and chemokines (interleukin [IL]-1α, IL-6, IL-10, and macrophage inflammatory protein 1 alpha [MIP-1α]) were increased; by 24 h, only MIP-1α remained elevated. ATP was not depleted, and adenosine correlated with 2′-cyclic AMP (cAMP), and not 5′-cAMP. Our data reveal (1) gene-array alterations similar to disorders of memory processing and a marked astrocyte response, (2) OS, (3) neuroinflammation with a sustained chemokine response, and (4) adenosine production despite lack of energy failure - possibly resulting from metabolism of 2′-3′-cAMP. A robust biochemical/molecular response occurs after blast-induced mTBI, with the body protected from blast and the head constrained to limit motion.

Original languageEnglish (US)
Pages (from-to)920-937
Number of pages18
JournalJournal of Neurotrauma
Volume30
Issue number11
DOIs
StatePublished - Jun 1 2013
Externally publishedYes

Fingerprint

Sulfhydryl Compounds
Adenosine Monophosphate
Chemokines
Cyclic AMP
Adenosine
Chemokine CCL3
Head
Memory Disorders
Wounds and Injuries
Brain
Astrocytes
Adenosine Triphosphate
Molecular Weight
Brain Concussion
Complement C1
Cytokines
Genes
Inosine
Purines
Helium

Keywords

  • adenosine
  • antioxidant
  • ascorbate
  • ATP
  • axonal injury
  • chemokine
  • combat casualty care
  • cyclic AMP
  • cytokine
  • gene array
  • glutathione
  • improvised explosive device
  • lipid peroxidation
  • multiplex
  • post-traumatic stress disorder
  • purine

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Screening of biochemical and molecular mechanisms of secondary injury and repair in the brain after experimental blast-induced traumatic brain injury in rats. / Kochanek, Patrick M.; Dixon, C. Edward; Shellington, David K.; Shin, Samuel S.; Bayir, Hülya; Jackson, Edwin K.; Kagan, Valerian E.; Yan, Hong Q.; Swauger, Peter V.; Parks, Steven A.; Ritzel, David V.; Bauman, Richard; Clark, Robert S.B.; Garman, Robert H.; Bandak, Faris; Ling, Geoffrey; Jenkins, Larry W.

In: Journal of Neurotrauma, Vol. 30, No. 11, 01.06.2013, p. 920-937.

Research output: Contribution to journalArticle

Kochanek, PM, Dixon, CE, Shellington, DK, Shin, SS, Bayir, H, Jackson, EK, Kagan, VE, Yan, HQ, Swauger, PV, Parks, SA, Ritzel, DV, Bauman, R, Clark, RSB, Garman, RH, Bandak, F, Ling, G & Jenkins, LW 2013, 'Screening of biochemical and molecular mechanisms of secondary injury and repair in the brain after experimental blast-induced traumatic brain injury in rats', Journal of Neurotrauma, vol. 30, no. 11, pp. 920-937. https://doi.org/10.1089/neu.2013.2862
Kochanek, Patrick M. ; Dixon, C. Edward ; Shellington, David K. ; Shin, Samuel S. ; Bayir, Hülya ; Jackson, Edwin K. ; Kagan, Valerian E. ; Yan, Hong Q. ; Swauger, Peter V. ; Parks, Steven A. ; Ritzel, David V. ; Bauman, Richard ; Clark, Robert S.B. ; Garman, Robert H. ; Bandak, Faris ; Ling, Geoffrey ; Jenkins, Larry W. / Screening of biochemical and molecular mechanisms of secondary injury and repair in the brain after experimental blast-induced traumatic brain injury in rats. In: Journal of Neurotrauma. 2013 ; Vol. 30, No. 11. pp. 920-937.
@article{466f549706d241079c9788f80887ce71,
title = "Screening of biochemical and molecular mechanisms of secondary injury and repair in the brain after experimental blast-induced traumatic brain injury in rats",
abstract = "Explosive blast-induced traumatic brain injury (TBI) is the signature insult in modern combat casualty care and has been linked to post-traumatic stress disorder, memory loss, and chronic traumatic encephalopathy. In this article we report on blast-induced mild TBI (mTBI) characterized by fiber-tract degeneration and axonal injury revealed by cupric silver staining in adult male rats after head-only exposure to 35 psi in a helium-driven shock tube with head restraint. We now explore pathways of secondary injury and repair using biochemical/molecular strategies. Injury produced ∼25{\%} mortality from apnea. Shams received identical anesthesia exposure. Rats were sacrificed at 2 or 24 h, and brain was sampled in the hippocampus and prefrontal cortex. Hippocampal samples were used to assess gene array (RatRef-12 Expression BeadChip; Illumina, Inc., San Diego, CA) and oxidative stress (OS; ascorbate, glutathione, low-molecular-weight thiols [LMWT], protein thiols, and 4-hydroxynonenal [HNE]). Cortical samples were used to assess neuroinflammation (cytokines, chemokines, and growth factors; Luminex Corporation, Austin, TX) and purines (adenosine triphosphate [ATP], adenosine diphosphate, adenosine, inosine, 2′-AMP [adenosine monophosphate], and 5′-AMP). Gene array revealed marked increases in astrocyte and neuroinflammatory markers at 24 h (glial fibrillary acidic protein, vimentin, and complement component 1) with expression patterns bioinformatically consistent with those noted in Alzheimer's disease and long-term potentiation. Ascorbate, LMWT, and protein thiols were reduced at 2 and 24 h; by 24 h, HNE was increased. At 2 h, multiple cytokines and chemokines (interleukin [IL]-1α, IL-6, IL-10, and macrophage inflammatory protein 1 alpha [MIP-1α]) were increased; by 24 h, only MIP-1α remained elevated. ATP was not depleted, and adenosine correlated with 2′-cyclic AMP (cAMP), and not 5′-cAMP. Our data reveal (1) gene-array alterations similar to disorders of memory processing and a marked astrocyte response, (2) OS, (3) neuroinflammation with a sustained chemokine response, and (4) adenosine production despite lack of energy failure - possibly resulting from metabolism of 2′-3′-cAMP. A robust biochemical/molecular response occurs after blast-induced mTBI, with the body protected from blast and the head constrained to limit motion.",
keywords = "adenosine, antioxidant, ascorbate, ATP, axonal injury, chemokine, combat casualty care, cyclic AMP, cytokine, gene array, glutathione, improvised explosive device, lipid peroxidation, multiplex, post-traumatic stress disorder, purine",
author = "Kochanek, {Patrick M.} and Dixon, {C. Edward} and Shellington, {David K.} and Shin, {Samuel S.} and H{\"u}lya Bayir and Jackson, {Edwin K.} and Kagan, {Valerian E.} and Yan, {Hong Q.} and Swauger, {Peter V.} and Parks, {Steven A.} and Ritzel, {David V.} and Richard Bauman and Clark, {Robert S.B.} and Garman, {Robert H.} and Faris Bandak and Geoffrey Ling and Jenkins, {Larry W.}",
year = "2013",
month = "6",
day = "1",
doi = "10.1089/neu.2013.2862",
language = "English (US)",
volume = "30",
pages = "920--937",
journal = "Journal of Neurotrauma",
issn = "0897-7151",
publisher = "Mary Ann Liebert Inc.",
number = "11",

}

TY - JOUR

T1 - Screening of biochemical and molecular mechanisms of secondary injury and repair in the brain after experimental blast-induced traumatic brain injury in rats

AU - Kochanek, Patrick M.

AU - Dixon, C. Edward

AU - Shellington, David K.

AU - Shin, Samuel S.

AU - Bayir, Hülya

AU - Jackson, Edwin K.

AU - Kagan, Valerian E.

AU - Yan, Hong Q.

AU - Swauger, Peter V.

AU - Parks, Steven A.

AU - Ritzel, David V.

AU - Bauman, Richard

AU - Clark, Robert S.B.

AU - Garman, Robert H.

AU - Bandak, Faris

AU - Ling, Geoffrey

AU - Jenkins, Larry W.

PY - 2013/6/1

Y1 - 2013/6/1

N2 - Explosive blast-induced traumatic brain injury (TBI) is the signature insult in modern combat casualty care and has been linked to post-traumatic stress disorder, memory loss, and chronic traumatic encephalopathy. In this article we report on blast-induced mild TBI (mTBI) characterized by fiber-tract degeneration and axonal injury revealed by cupric silver staining in adult male rats after head-only exposure to 35 psi in a helium-driven shock tube with head restraint. We now explore pathways of secondary injury and repair using biochemical/molecular strategies. Injury produced ∼25% mortality from apnea. Shams received identical anesthesia exposure. Rats were sacrificed at 2 or 24 h, and brain was sampled in the hippocampus and prefrontal cortex. Hippocampal samples were used to assess gene array (RatRef-12 Expression BeadChip; Illumina, Inc., San Diego, CA) and oxidative stress (OS; ascorbate, glutathione, low-molecular-weight thiols [LMWT], protein thiols, and 4-hydroxynonenal [HNE]). Cortical samples were used to assess neuroinflammation (cytokines, chemokines, and growth factors; Luminex Corporation, Austin, TX) and purines (adenosine triphosphate [ATP], adenosine diphosphate, adenosine, inosine, 2′-AMP [adenosine monophosphate], and 5′-AMP). Gene array revealed marked increases in astrocyte and neuroinflammatory markers at 24 h (glial fibrillary acidic protein, vimentin, and complement component 1) with expression patterns bioinformatically consistent with those noted in Alzheimer's disease and long-term potentiation. Ascorbate, LMWT, and protein thiols were reduced at 2 and 24 h; by 24 h, HNE was increased. At 2 h, multiple cytokines and chemokines (interleukin [IL]-1α, IL-6, IL-10, and macrophage inflammatory protein 1 alpha [MIP-1α]) were increased; by 24 h, only MIP-1α remained elevated. ATP was not depleted, and adenosine correlated with 2′-cyclic AMP (cAMP), and not 5′-cAMP. Our data reveal (1) gene-array alterations similar to disorders of memory processing and a marked astrocyte response, (2) OS, (3) neuroinflammation with a sustained chemokine response, and (4) adenosine production despite lack of energy failure - possibly resulting from metabolism of 2′-3′-cAMP. A robust biochemical/molecular response occurs after blast-induced mTBI, with the body protected from blast and the head constrained to limit motion.

AB - Explosive blast-induced traumatic brain injury (TBI) is the signature insult in modern combat casualty care and has been linked to post-traumatic stress disorder, memory loss, and chronic traumatic encephalopathy. In this article we report on blast-induced mild TBI (mTBI) characterized by fiber-tract degeneration and axonal injury revealed by cupric silver staining in adult male rats after head-only exposure to 35 psi in a helium-driven shock tube with head restraint. We now explore pathways of secondary injury and repair using biochemical/molecular strategies. Injury produced ∼25% mortality from apnea. Shams received identical anesthesia exposure. Rats were sacrificed at 2 or 24 h, and brain was sampled in the hippocampus and prefrontal cortex. Hippocampal samples were used to assess gene array (RatRef-12 Expression BeadChip; Illumina, Inc., San Diego, CA) and oxidative stress (OS; ascorbate, glutathione, low-molecular-weight thiols [LMWT], protein thiols, and 4-hydroxynonenal [HNE]). Cortical samples were used to assess neuroinflammation (cytokines, chemokines, and growth factors; Luminex Corporation, Austin, TX) and purines (adenosine triphosphate [ATP], adenosine diphosphate, adenosine, inosine, 2′-AMP [adenosine monophosphate], and 5′-AMP). Gene array revealed marked increases in astrocyte and neuroinflammatory markers at 24 h (glial fibrillary acidic protein, vimentin, and complement component 1) with expression patterns bioinformatically consistent with those noted in Alzheimer's disease and long-term potentiation. Ascorbate, LMWT, and protein thiols were reduced at 2 and 24 h; by 24 h, HNE was increased. At 2 h, multiple cytokines and chemokines (interleukin [IL]-1α, IL-6, IL-10, and macrophage inflammatory protein 1 alpha [MIP-1α]) were increased; by 24 h, only MIP-1α remained elevated. ATP was not depleted, and adenosine correlated with 2′-cyclic AMP (cAMP), and not 5′-cAMP. Our data reveal (1) gene-array alterations similar to disorders of memory processing and a marked astrocyte response, (2) OS, (3) neuroinflammation with a sustained chemokine response, and (4) adenosine production despite lack of energy failure - possibly resulting from metabolism of 2′-3′-cAMP. A robust biochemical/molecular response occurs after blast-induced mTBI, with the body protected from blast and the head constrained to limit motion.

KW - adenosine

KW - antioxidant

KW - ascorbate

KW - ATP

KW - axonal injury

KW - chemokine

KW - combat casualty care

KW - cyclic AMP

KW - cytokine

KW - gene array

KW - glutathione

KW - improvised explosive device

KW - lipid peroxidation

KW - multiplex

KW - post-traumatic stress disorder

KW - purine

UR - http://www.scopus.com/inward/record.url?scp=84879987191&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879987191&partnerID=8YFLogxK

U2 - 10.1089/neu.2013.2862

DO - 10.1089/neu.2013.2862

M3 - Article

C2 - 23496248

AN - SCOPUS:84879987191

VL - 30

SP - 920

EP - 937

JO - Journal of Neurotrauma

JF - Journal of Neurotrauma

SN - 0897-7151

IS - 11

ER -