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: 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.
authors.affiliation: Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA. kochanekpm@ccm.upmc.edu
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
authors.forename: C Edward
authors.initials: CE
authors.lastname: Dixon
authors.forename: David K
authors.initials: DK
authors.lastname: Shellington
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Shin
authors.forename: Hülya
authors.initials: H
authors.lastname: Bayır
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
authors.forename: Valerian E
authors.initials: VE
authors.lastname: Kagan
authors.forename: Hong Q
authors.initials: HQ
authors.lastname: Yan
authors.forename: Peter V
authors.initials: PV
authors.lastname: Swauger
authors.forename: Steven A
authors.initials: SA
authors.lastname: Parks
authors.forename: David V
authors.initials: DV
authors.lastname: Ritzel
authors.forename: Richard
authors.initials: R
authors.lastname: Bauman
authors.forename: Robert S B
authors.initials: RS
authors.lastname: Clark
authors.forename: Robert H
authors.initials: RH
authors.lastname: Garman
authors.forename: Faris
authors.initials: F
authors.lastname: Bandak
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Ling
authors.forename: Larry W
authors.initials: LW
authors.lastname: Jenkins
mesh_terms: D000818:Animals; D001753:Blast Injuries / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D008297:Male; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009416:Nerve Regeneration / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D059467:Transcriptome