Investigation of blast induced neurotrauma in a rodent models

CHAPTER INTRODUCTION 1.1 Overview of Traumatic Brain Injury Traumatic brain injury (TBI) is one of the foremost causes of disability and death in both civilian settings and theatres of war TBI can be simply defined as damage to the brain tissue resulting from external mechanical forces (Center for Disease Control)(CDC)) In terms of gross clinical classification, TBI can be further sub-classified as penetrating or closed head injury TBI severity ranges from mild to moderate to severe TBI severity is clinically determined using the Glasgow Coma Scale (GCS), which assesses the conscious state of a TBI patient in terms of eye, verbal and motor responses The severity of TBI using the GCS is categorised as mild (GCS >13), moderate (GCS - 12) and severe (GCS 30min and 24 hrs, Severity based on other criteria >1 day and 24hrs > 24 hrs, Severity based on other criteria >7days 13-15 9-12 600KPa 0.05~0.1ms NA 3m BL Body armoured 183.89±4.57 0.8±0.02 55.242.62 2m BH Body armoured 477.19±41.59 0.39±0.10 67.03±8.76 0% 0% 11.1±3.5% 28.4±2.8% No deficit ↑error @ 5d & 2w ↑ error @ 6d NA No deficit No deficit No deficit No deficit 5d and 1mth mth NA NA No deficit No deficit No deficit No deficit 4d, 6d, 7d, mth 6d, 7d NA NA No deficit No deficit No deficit No deficit 3d ↑ anxiety NA NA NA Proinflammatory ↑IL-1α at 2w Slight ↑ (not significant ) for others All increased at 2w in serum ↑in serum and cortex at 72h and serum at 1m ↑ in hippo at 24hrs, persist up to w Antiinflammatory Slight ↑ in IL-10 at 2w ↑CINC-1@ 3h ↑IL-10 @ 2w iSTAT NA NA NR2 NA NA ↑IL-1α and IL-2 at 72h in serum ↑ all in cortex at 24h ↑ IL-2, IL-12 @24h up to w IFNγ and ↑IL-1β at 1m ↑IL-10 @ 72h serum, ↑all@24h in Cortex, ↑IL-4 at 24h and IL-13 at 1m I Hippo ↑PO2, TCO2@ 2w, ↑ lactate 1m ↑ @ 2w Histology NA ↑Neurodegeneration, ↑AQP-4 up to 72h ↑microglia activation, ↑axonal injury ↑Neuronal injury @ 72h, lesser @ 2w and m , ↑CA3 injury @ 72h Slight DG injury at 2w, ↑ thalamic injury @ 72h and 2w, ↑diffuse axonal injury in cortex and hippo @ 24h to 2w ↑ Extensive neuronal injury @ 24h and 72h, less @ 2w and 1m, ↑CA3 and DG injury @ 72h to 1m, ↑ thalamic injury from 24h to w, ↑diffuse axonal injury in cortex and hippo @ 24h to 2w Pressure Duration (ms) Impulse (KPams-1) Mortality Behavioral RAM choice Biomarkers Cytokines Blood Reference Mem Working Mem Sustained attention Impulsivity Inhibition control EPM Beam Walk 2g No protection 240kPa NA NA 5g Body armoured ↑at 72h and 1m in serum, ↑ IL4, 13 @ 24h in Hippo ↑creatinine 24h ↑ @ 2w 110 Fig 84 Diffuse Axonal Injury - Low Neuronal Injury Inflammation Behavioral Changes 5g BA >600kPa, 0.05ms 24h 72h 1w 2w Injury Metabolic Changes/NR2 Fig 85 Diffuse Axonal Injury Neuronal Injury Inflammation Tissue Inflammation systemic 3m BL Behavioral / Cognitive Changes 184kPa, 0.8ms 24h 72h 1w 2w 1m Injury Fig 86 Metabolic Changes NR2 Diffuse Axonal Injury Neuronal Injury Inflammation Tissue Inflammation systemic Inflammation systemic Behavioral / Cognitive Changes???? 2m BH 477kPa, 0.4ms 24h 72h 1w 2w 1m Injury 111 5.1 Limitations of the study Due to the enormous amount of logistics difficulty in conducting experiments using real explosives, this had numerous limitations that precluded a full-fledged study from being carried out Firstly, the shock tube model was investigated and utilized in Sweden where the limitation in manpower and time duration did not allow us the opportunity to carry out repeated testing hence, not enough samples were collected to carry out extensive investigations such as the cytokine changes in the cerebral tissue In addition, failure of pressure sensors prevented us from characterizing the blast the pressure profile to correlate with histological, cognitive and systemic findings For the open field model study, behavioural training was not completed for the 2m BH group and this resulted in incomplete understanding of the histopathological and systemic cytokines expressions that could have led to the hypothesized varying degree of cognitive and behavioural changes In addition, the original planning to extend the behavioural assessments to up to months was not possible due to limitation of blast site and animal facilities and hence, was limited to month assessment This restricted us from understanding long term cognitive and behavioural changes which would have provided better representation of the clinical scenario Although efforts to provide a comprehensive and comparable comparison between the two models were made, limitations still exists However, an overview of equating specific blast pressure profile to varying effects on the brain was provided 112 Annex A: List of BINT research investigated on varying experimental animals, blast source and blast pressure parameters Study A mouse model of blast-induced mild traumatic brain injury Vardit Rubovitch, Meital Ten-Bosch, Ofer Zohar, Catherine R Harrison, Catherine Tempel-Brami, Elliot Stein, Barry J Hoffer, Carey D Balaban, Shaul Schreiber, Wen-Ta Chiu, Chaim G Pick Experimental Neurology, Volume 232, Issue 2, December 2011, Pages 280-289 Neuroprotective role of aminoguanidine in behavioral changes after blast injury Moochhala SM, Md S, Lu J, Teng CH, Greengrass C J Trauma 2004 Feb;56(2):393-403 Neuropathology and pressure in the pig brain resulting from low-impulse noise exposure Säljö A, Arrhén F, Bolouri H, Mayorga M, Hamberger A J Neurotrauma 2008 Dec;25(12):1397-406 Low-level blasts raise intracranial pressure and impair cognitive function in rats Säljö A, Svensson B, Mayorga M, Hamberger A, Bolouri H J Neurotrauma 2009 Aug;26(8):1345-52 Measurement of blast wave by a miniature fiber optic pressure transducer in the rat brain J Neurosci Methods 2007 Jan 30;159(2):277-81 Epub 2006 Sep Chavko M, Koller WA, Prusaczyk WK, McCarron RM Low level primary blast injury in rodent brain Pun PB, Kan EM, Salim A, Li Z, Ng KC, Moochhala SM, Ling EA, Tan MH, Lu J Front Neurol 2011 Apr 4;2:19 Rapid release of tissue enzymes into blood after blast exposure: potential use as biological dosimeters Arun P, Oguntayo S, Alamneh Y, Honnold C, Wang Y, Valiyaveettil M, Long JB, Nambiar MP PLoS One 2012;7(4) Animal Mice Type Open field chemical explosive, no protection, Blast pressure 17 ~ 38 KPa Rat Chemical explosive, body unshielded but animals behind wall 20KPa Swine Weapons and shocktube, chemical 9-23KPa in air, 128-482 KPa in water Rat Blast tube, chemical charge, Rat Pneumatic shock tube No protection 10, 30, and 60 kPa, 4–6 msec duration 40±7 kPa Rat 120 Kg TNT, head on, no shielding Head orientation affects the intracranial pressure response resulting from shock wave loading in the rat Dal Cengio Leonardi A, Keane NJ, Bir CA, Ryan AG, Xu L, Vandevord PJ J Biomech 2012 Oct 11;45(15):2595-602 Blast-induced tinnitus and hearing loss in rats: behavioral and imaging assays Mao JC, Pace E, Pierozynski P, Kou Z, Shen Y, VandeVord P, Haacke EM, Zhang X, Zhang J J Neurotrauma 2012 Jan 20;29(2):430-44 Effect of blast exposure on the brain structure and cognition in Macaca fascicularis Lu J, Ng KC, Ling G, Wu J, Poon DJ, Kan EM, Tan MH, Wu YJ, Li P, Moochhala S, Yap E, Lee LK, Teo M, Yeh IB, Sergio DM, Chua F, Kumar SD, Ling EA Effects of variable blast pressures on blood flow and oxygen saturation in rat brain as evidenced using MRI Rat Pneumatic shock tube Frontal facing, body shielded 70KPa, at various orientation Rat Pneumatic shock tube No protection Frontal facing 95 kPa 120 Kg TNT, head on, no shielding 80KPa , 13.5ms duration 197KPa, 9.3ms duration Pneumatic shock tube 90, 103, 117, 159 and 193 kPa Mice Nonhuman primates Rat Pneumatic shock tube No protection 48.9KPa with 14.5ms duration 77.3KPa with 18.2 duration 69, 103 and 145KPa, repeated blast at 1or 30mins interval 113 Bir C, Vandevord P, Shen Y, Raza W, Haacke EM Magn Reson Imaging 2012 May;30(4):527-34 Epub 2012 Jan 27 Mild neurotrauma indicates a range-specific pressure response to low level shock wave exposure Vandevord PJ, Bolander R, Sajja VS, Hay K, Bir CA Ann Biomed Eng 2012 Jan;40(1):227-36 Epub 2011 Oct 13 Assessment of the effects of acute and repeated exposure to blast overpressure in rodents: toward agreater understanding of blast and the potential ramifications for injury in humans exposed to blast Ahlers ST, Vasserman-Stokes E, Shaughness MC, Hall AA, Shear DA, Chavko M, McCarron RM, Stone JR Front Neurol 2012;3:32 Epub 2012 Mar Skull flexure as a contributing factor in the mechanism of injury in the rat when exposed to a shock wave Bolander R, Mathie B, Bir C, Ritzel D, VandeVord P Ann Biomed Eng 2011 Oct;39(10):2550-9 Epub 2011 Jul MicroRNA let-7i is a promising serum biomarker for blastinduced traumatic brain injury Balakathiresan N, Bhomia M, Chandran R, Chavko M, McCarron RM, Maheshwari RK J Neurotrauma 2012 May 1;29(7):1379-87 Epub 2012 Apr 13 Blast-induced moderate neurotrauma (BINT) elicits early complement activation and tumor necrosis factor alpha (TNFα) release in a rat brain Dalle Lucca JJ, Chavko M, Dubick MA, Adeeb S, Falabella MJ, Slack JL, McCarron R, Li Y J Neurol Sci 2012 Jul 15;318(1-2):146-54 Blast overpressure in rats: recreating a battlefield injury in the laboratory Long JB, Bentley TL, Wessner KA, Cerone C, Sweeney S, Bauman RA J Neurotrauma 2009 Jun;26(6):827-40 Regional specific alterations in brain acetylcholinesterase activity after repeated blastexposures in mice Valiyaveettil M, Alamneh Y, Oguntayo S, Wei Y, Wang Y, Arun P, Nambiar MP.Neurosci Lett 2012 Jan 6;506(1):141-5 Epub 2011 Nov Increase in blood-brain barrier permeability, oxidative stress, and activated microglia in a rat model of blastinduced traumatic brain injury Readnower RD, Chavko M, Adeeb S, Conroy MD, Pauly JR, McCarron RM, Sullivan PG J Neurosci Res 2010 Dec;88(16):3530-9 doi: 10.1002/jnr.22510 Epub 2010 Sep 29 Rat No protection Frontal facing Pneumatic shock tube No protection 97, 117, or 153 KPa Rat Pneumatic shock tube No protection Rat Pneumatic shock tube frontal facing, No protection Rat Pneumatic shock tube No protection 120 KPa x times in 2hrs 120 KPa x times interval of 24hrs Rat Pneumatic shock tube No protection 120±7 kPa Rat Pneumatic shock tube with Kevlar shielding exposing head only Side profile Some with blast and controlled hemorrhage Pneumatic shock tube No protection 114, 126 and 147 kPa Pneumatic shock tube, side facing 120 kPa Mice Rat 36.6, 74.5, and 116.7 kPa 36.6 KPa with duration 4.1ms, impulse 75.2PKa/ms 74.5 with duration 4.8 ms, impulse 175.8 PKa/ms 116.7 KPa with duration 6.8ms, impulse 335.5 PKa/ms 69, 97, 117, and 172 kPa 142KPa multiple exposure three times with or 30 intervals 114 A multi-mode shock tube for investigation of blast-induced traumatic brain injury Reneer DV, Hisel RD, Hoffman JM, Kryscio RJ, Lusk BT, Geddes JW J Neurotrauma 2011 Jan;28(1):95-104 Stress and traumatic brain injury: a behavioral, proteomics, and histological study Kwon SK, Kovesdi E, Gyorgy AB, Wingo D, Kamnaksh A, Walker J, Long JB, Agoston DV Front Neurol 2011 Mar 7;2:12 The effect of enriched environment on the outcome of traumatic brain injury; a behavioral, proteomics, and histological study Kovesdi E, Gyorgy AB, Kwon SK, Wingo DL, Kamnaksh A, Long JB, Kasper CE, Agoston DV Front Neurosci 2011 Apr 1;5:42 A mouse model of blast injury to brain: initial pathological, neuropathological, and behavioral characterization Koliatsos VE, Cernak I, Xu L, Song Y, Savonenko A, Crain BJ, Eberhart CG, Frangakis CE, Melnikova T, Kim H, Lee D J Neuropathol Exp Neurol 2011 May;70(5):399-416 The pathobiology of blast injuries and blast-induced neurotrauma as identified using a new experimental model of injury in mice Cernak I, Merkle AC, Koliatsos VE, Bilik JM, Luong QT, Mahota TM, Xu L, Slack N, Windle D, Ahmed FA Neurobiol Dis 2011 Feb;41(2):538-51 Epub 2010 Nov 11 Rat Pneumatic shock tube side facing No protection Rat Pneumatic shock tube side facing No protection Rat using a compression-driven shock tube No shielding front facing 142±27KPa Mice Pneumatic shock tube No protection, supine or at the prone position Pneumatic shock tube supine or at the prone position, selective shielding 172 and 310 kPag Mice Development of a rat model for studying blast-induced traumatic brain injury Cheng J, Gu J, Ma Y, Yang T, Kuang Y, Li B, Kang J J Neurol Sci 2010 Jul 15;294(1-2):23-8 Epub 2010 May 16 Rat Blast exposure causes redistribution of phosphorylated neurofilament subunits in neurons of the adult rat brain Säljö A, Bao F, Haglid KG, Hansson HA J Neurotrauma 2000 Aug;17(8):719-26 Rat An introductory characterization of a combat-casualty-care relevant swine model of closed headinjury resulting from exposure to explosive blast Bauman RA, Ling G, Tong L, Januszkiewicz A, Agoston D, Delanerolle N, Kim Y, Ritzel D, Bell R, Ecklund J, Armonda R, Bandak F, Parks S J Neurotrauma 2009 Jun;26(6):841-60 Characteristics of an explosive blast-induced brain injury in an experimental model de Lanerolle NC, Bandak F, Kang D, Li AY, Du F, Swauger P, Parks S, Ling G, Kim JH J Neuropathol Exp Neurol 2011 Nov;70(11):1046-57 Time-dependent changes in serum biomarker levels after blast traumatic brain injury Open field, chemical explosive equivalent of 400 mg TNT, occipital portion of the head facing the blast Blast tube, chemical charge, 0.5 and 2g Side prone 100, 150, or 200kPa peak overpressure Body shielded by metal tube 142±27KPa Mild-183± 14, moderate213±17, severe295 ±32 Impulse: Mild 345 ±34, moderate352±145, severe496 ±117 103, 200 to 396 kPa, No duration provided 154±2.2 kPa, duration of 1.7± 0.1 msec 240±3.4 kPa, duration 2±0.2 msec Not shown, moderate Swine Chemical blast tube , Side with kelvar armour Swine Chemical blast tube , Tube, and structures 241KPa – 434KPa Swine Chemical blast tube , 276PKa Rats Pneumatic shock tube Cranial directed, no protection 358 kPa, 10 msec duration Swine 40 and 50 kg Chemical blast tube 193KPa and 324KPa Helium-driven shock tube, side facing 240KPa with msec duration 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cell death triggered by traumatic brain injury Critical Care 9:66 120 [...]... decreased performance on the radial arm maze Reward dish Central Arena Fig 9: Overhead view of the Radial Arm Maze and MazeSoft software 20 The RAM (Panlab, Spain) consists of an octagonal central platform with eight automated sliding guillotine doors giving access to eight radiating arms of equal lengths (Wx1690mm, Lx1250mm, Hx1450mm)(Fig 9) The apparatus is made of black plexiglas and mounted on a tripod... post -blast (Fig 12) In contrast, 2g blast animals showed similar minimal working memory errors compared to sham animals However, 5g blast animals did not show any deficits at 2 weeks post -blast and were similar to 2g blast and sham animals Radial Arm Maze - Working Memory Error No of Errors 2.0 1.5 1.0 * 0.5 0.0 Baseline 2g Blast 3d aft injury 4d aft injury 5d aft injury 6d aft injury 7d aft injury... in (GFAP) astrocytes and serves as a cell specific marker that distinguishes differentiated astrocytes from other glial cells Ionized calcium-binding A calcium-binding protein that play a role in macrophage adapter molecule 1 (IBA-1) activation and function and is a marker of microglia Aquaporin 4 (AQP-4) Water channels expressed in astrocytes and AQP427 mediated water flux represents an integral element... also generally able to master the beam walking task in a shorter time (i.e within a day), as compared to the long training period required to achieve baseline performance on the rotarod 1m 0.5m Goalbox A B C ~30cm Foam cushion Fig 10: Laboratory set-up of Beam Walk Apparatus The apparatus used in the beam-walking test is very basic It consists mainly of a narrow flat beam (2.5cm wide) leading to a brightly... error after blast 4.0 Radial Arm Maze - Reference Memory Error No of Errors 3.0 2.0 * # 1.0 0.0 Baseline 2g Blast 3d aft injury 4d aft injury 5d aft injury 6d aft injury 7d aft injury 2wk aft injury Sham 5g BA Timepoints Fig 13: Radial Arm Maze: Reference memory error of sham (red), 2 g blast (blue) and 5 g BA blast (green) animals before and up to 2 weeks post -blast 5 g BA animals had significantly increased... Specific Inflammatory cytokines assay The relative concentrations of 12 pro-inflammatory cytokines to control samples in the protein supernatant from the cortex and cerebellum tissue lysate of rats at designated time-points after blast injury were determined with a Rat Inflammatory Cytokines Multi-Analyte ELISArray kit (Mer00 4A, Qiagen, CA, USA) The tissue homogenates for the ELISArray measurements... coordination) and 5CSRTT (test sustained attention) were carried out as detailed below Baseline performance was established prior to injury exposure and behavioral testing was carried out after blast exposure until sacrifice at up to 1 month after injury 2.311 Radial Arm Maze The radial arm maze (RAM, Fig 9) is a common tool used to investigate and measure specific aspects of spatial working and reference... allows us to examine a more specific blast overpressure spectrum by varying distance from blast source and pressure characteristics that can result in blast induced brain injury This model was established at ATREC Pte Ltd, Singapore Explosives tests were conducted in a 10 by 10m concrete and steel reinforced room 2.21 Animal subjects Male Sprague-Dawley rats (NUS CARE (Singapore) and ARC (Australia)... Blast (green) animals before and up to 2 weeks post -blast Time taken to visit the correct arms were increased at 4 days after blast for 5g BA groups compared to Sham and 2g Blast * = p ... Overview of Traumatic Brain Injury Traumatic brain injury (TBI) is one of the foremost causes of disability and death in both civilian settings and theatres of war TBI can be simply defined as damage... resulting in focal injuries at both sides of the brain These acceleration/deceleration forces can also cause stretching and shearing of the brain tissue when rotational forces are involved In addition,... during task training Subjects are also generally able to master the beam walking task in a shorter time (i.e within a day), as compared to the long training period required to achieve baseline