Effects of Antioxidant Treatment on Blast-Induced Brain Injury

Blast-induced traumatic brain injury has dramatically increased in combat troops in today’s military operations. We previously reported that antioxidant treatment can provide protection to the peripheral auditory end organ, the cochlea. In the present study, we examined biomarker expression in the brains of rats at different time points (3 hours to 21 days) after three successive 14 psi blast overpressure exposures to evaluate antioxidant treatment effects on blast-induced brain injury. Rats in the treatment groups received a combination of antioxidants (2,4-disulfonyl α-phenyl tertiary butyl nitrone and N-acetylcysteine) one hour after blast exposure and then twice a day for the following two days. The biomarkers examined included an oxidative stress marker (4-hydroxy-2-nonenal, 4-HNE), an immediate early gene (c-fos), a neural injury marker (glial fibrillary acidic protein, GFAP) and two axonal injury markers [amyloid beta (A4) precursor protein, APP, and 68 kDa neurofilament, NF-68]. The results demonstrate that blast exposure induced or up-regulated the following: 4-HNE production in the dorsal hippocampus commissure and the forceps major corpus callosum near the lateral ventricle; c-fos and GFAP expression in most regions of the brain, including the retrosplenial cortex, the hippocampus, the cochlear nucleus, and the inferior colliculus; and NF-68 and APP expression in the hippocampus, the auditory cortex, and the medial geniculate nucleus (MGN). Antioxidant treatment reduced the following: 4-HNE in the hippocampus and the forceps major corpus callosum, c-fos expression in the retrosplenial cortex, GFAP expression in the dorsal cochlear nucleus (DCN), and APP and NF-68 expression in the hippocampus, auditory cortex, and MGN. This preliminary study indicates that antioxidant treatment may provide therapeutic protection to the central auditory pathway (the DCN and MGN) and the non-auditory central nervous system (hippocampus and retrosplenial cortex), suggesting that these compounds have the potential to simultaneously treat blast-induced injuries in the brain and auditory system.     

A computational model of blast loading on the human eye

Ocular injuries from blast have increased in recent wars, but the injury mechanism associated with the primary blast wave is unknown. We employ a three-dimensional fluid–structure interaction computational model to understand the stresses and deformations incurred by the globe due to blast overpressure. Our numerical results demonstrate that the blast wave reflections off the facial features around the eye increase the pressure loading on and around the eye. The blast wave produces asymmetric loading on the eye, which causes globe distortion. The deformation response of the globe under blast loading was evaluated, and regions of high stresses and strains inside the globe were identified. Our numerical results show that the blast loading results in globe distortion and large deviatoric stresses in the sclera. These large deviatoric stresses may be indicator for the risk of interfacial failure between the tissues of the sclera and the orbit.     

Androgenic regulation of the central glia response following nerve damage.

Current research on the effects of gonadal steroids on the brain and spinal cord indicates that these agents have profound trophic effects on many aspects of neuronal functioning, including cell survival, growth and metabolism, elaboration of processes, synaptogenesis, and neurotransmission (Jones et al., 1985; Luine, 1985; Nordeen et al., 1985; Matsumoto et al., 1988a,b; Gould et al., 1990). Since many of the aspects of normal neuronal functioning altered by gonadal steroids are affected by injury to the nervous system, we initiated a series of experiments designed to exploit the trophic capabilities of steroids as therapeutic agents in neuronal injury and repair (Kujawa et al., 1989, 1991; Kujawa and Jones, 1990). Three steroid-sensitive model systems were used for these studies: the hamster facial motoneuron, the rat sciatic motoneuron, and the hamster rubrospinal motoneuron. The results of our initial series of experiments suggest that androgens, and possibly estrogens, act either directly or indirectly on the injured motoneuron and enhance elements of the neuronal reparative response that are critical to successful recovery of function. Recently, we discovered that gonadal steroids may also modulate the central glia response to nerve damage. In this review, a summary of our data identifying a therapeutic role for androgens in enhancing the reparative response of motoneurons to injury is presented. This is followed by a discussion of the effects of androgens on the glial response to injury.     

Rapid release of tissue enzymes into blood after blast exposure: potential use as biological dosimeters

Explosive blast results in multiple organ injury and polytrauma, the intensity of which varies with the nature of the exposure, orientation, environment and individual resilience. Blast overpressure alone may not precisely indicate the level of body or brain injury after blast exposure. Assessment of the extent of body injury after blast exposure is important, since polytrauma and systemic factors significantly contribute to blast-induced traumatic brain injury. We evaluated the activity of plasma enzymes including aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and creatine kinase (CK) at different time points after blast exposure using a mouse model of single and repeated blast exposures to assess the severity of injury. Our data show that activities of all the enzymes in the plasma were significantly increased as early as 1 h after blast exposure. The elevated enzyme activity remained up to 6 h in an overpressure dose-dependent manner and returned close to normal levels at 24 h. Head-only blast exposure with body protection showed no increase in the enzyme activities suggesting that brain injury alone does not contribute to the systemic increase. In contrast to plasma increase, AST, ALT and LDH activity in the liver and CK in the skeletal muscle showed drastic decrease at 6 h after blast exposures. Histopathology showed mild necrosis at 6 h and severe necrosis at 24 h after blast exposures in liver and no changes in the skeletal muscle suggesting that the enzyme release from the tissue to plasma is probably triggered by transient cell membrane disruption from shockwave and not due to necrosis. Overpressure dependent transient release of tissue enzymes and elevation in the plasma after blast exposure suggest that elevated enzyme activities in the blood can be potentially used as a biological dosimeter to assess the severity of blast injury.     

The role of stress waves in thoracic visceral injury from blast loading: modification of stress transmission by foams and high-density materials

Materials have been applied to the thoracic wall of anaesthetised experimental animals exposed to blast overpressure to investigate the coupling of direct stress waves into the thorax and the relative contribution of compressive stress waves and gross thoracic compression to lung injury. The ultimate purpose of the work is to develop effective personal protection from the primary effects of blast overpressure--efficient protection can only be achieved if the injury mechanism is identified and characterized. Foam materials acted as acoustic couplers and resulted in a significant augmentation of the visceral injury; decoupling and elimination of injury were achieved by application of a high acoustic impedance layer on top of the foam. In vitro experiments studying stress wave transmission from air through various layers into an anechoic water chamber showed a significant increase in power transmitted by the foams, principally at high frequencies. Material such as copper or resin bonded Kevlar incorporated as a facing upon the foam achieved substantial decoupling at high frequencies--low frequency transmission was largely unaffected. An acoustic transmission model replicated the coupling of the blast waves into the anechoic water chamber. The studies suggest that direct transmission of stress waves plays a dominant role in lung parenchymal injury from blast loading and that gross thoracic compression is not the primary injury mechanism. Acoustic decoupling principles may therefore be employed to reduce the direct stress coupled into the body and thus reduce the severity of lung injury--the most simple decoupler is a high acoustic impedance material as a facing upon a foam, but decoupling layers may be optimized using acoustic transmission models. Conventional impacts producing high body wall velocities will also lead to stress wave generation and transmission--stress wave effects may dominate the visceral response to the impact with direct compression and shear contributing little to the aetiology of the injury.     

Shear forces during blast, not abrupt changes in pressure alone, generate calcium activity in human brain cells

Blast-Induced Traumatic Brain Injury (bTBI) describes a spectrum of injuries caused by an explosive force that results in changes in brain function. The mechanism responsible for primary bTBI following a blast shockwave remains unknown. We have developed a pneumatic device that delivers shockwaves, similar to those known to induce bTBI, within a chamber optimal for fluorescence microscopy. Abrupt changes in pressure can be created with and without the presence of shear forces at the surface of cells. In primary cultures of human central nervous system cells, the cellular calcium response to shockwaves alone was negligible. Even when the applied pressure reached 15 atm, there was no damage or excitation, unless concomitant shear forces, peaking between 0.3 to 0.7 Pa, were present at the cell surface. The probability of cellular injury in response to a shockwave was low and cell survival was unaffected 20 hours after shockwave exposure.     

Changes in Diffusion Kurtosis Imaging and Magnetic Resonance Spectroscopy in a Direct Cranial Blast Traumatic Brain Injury (dc-bTBI) Model

Explosive blast-related injuries are one of the hallmark injuries of veterans returning from recent wars, but the effects of a blast overpressure on the brain are poorly understood. In this study, we used in vivo diffusion kurtosis imaging (DKI) and proton magnetic resonance spectroscopy (MRS) to investigate tissue microstructure and metabolic changes in a novel, direct cranial blast traumatic brain injury (dc-bTBI) rat model. Imaging was performed on rats before injury and 1, 7, 14 and 28 days after blast exposure (~517 kPa peak overpressure to the dorsum of the head). No brain parenchyma abnormalities were visible on conventional T2-weighted MRI, but microstructural and metabolic changes were observed with DKI and proton MRS, respectively. Increased mean kurtosis, which peaked at 21 days post injury, was observed in the hippocampus and the internal capsule. Concomitant increases in myo-Inositol (Ins) and Taurine (Tau) were also observed in the hippocampus, while early changes at 1 day in the Glutamine (Gln) were observed in the internal capsule, all indicating glial abnormality in these regions. Neurofunctional testing on a separate but similarly treated group of rats showed early disturbances in vestibulomotor functions (days 1–14), which were associated with imaging changes in the internal capsule. Delayed impairments in spatial memory and in rapid learning, as assessed by Morris Water Maze paradigms (days 14–19), were associated with delayed changes in the hippocampus. Significant microglial activation and neurodegeneration were observed at 28 days in the hippocampus. Overall, our findings indicate delayed neurofunctional and pathological abnormalities following dc-bTBI that are silent on conventional T2-weighted imaging, but are detectable using DKI and proton MRS.     

Blast shock wave mitigation using the hydraulic energy redirection and release technology

A hydraulic energy redirection and release technology has been developed for mitigating the effects of blast shock waves on protected objects. The technology employs a liquid-filled plastic tubing as a blast overpressure transformer to transfer kinetic energy of blast shock waves into hydraulic energy in the plastic tubings. The hydraulic energy is redirected through the plastic tubings to the openings at the lower ends, and then is quickly released with the liquid flowing out through the openings. The samples of the specifically designed body armor in which the liquid-filled plastic tubings were installed vertically as the outer layer of the body armor were tested. The blast test results demonstrated that blast overpressure behind the body armor samples was remarkably reduced by 97% in 0.2 msec after the liquid flowed out of its appropriate volume through the openings. The results also suggested that a volumetric liquid surge might be created when kinetic energy of blast shock wave was transferred into hydraulic energy to cause a rapid physical movement or displacement of the liquid. The volumetric liquid surge has a strong destructive power, and can cause a noncontact, remote injury in humans (such as blast-induced traumatic brain injury and post-traumatic stress disorder) if it is created in cardiovascular system. The hydraulic energy redirection and release technology can successfully mitigate blast shock waves from the outer surface of the body armor. It should be further explored as an innovative approach to effectively protect against blast threats to civilian and military personnel.     

Computational Study of Human Head Response to Primary Blast Waves of Five Levels from Three Directions

Human exposure to blast waves without any fragment impacts can still result in primary blast-induced traumatic brain injury (bTBI). To investigate the mechanical response of human brain to primary blast waves and to identify the injury mechanisms of bTBI, a three-dimensional finite element head model consisting of the scalp, skull, cerebrospinal fluid, nasal cavity, and brain was developed from the imaging data set of a human female. The finite element head model was partially validated and was subjected to the blast waves of five blast intensities from the anterior, right lateral, and posterior directions at a stand-off distance of one meter from the detonation center. Simulation results show that the blast wave directly transmits into the head and causes a pressure wave propagating through the brain tissue. Intracranial pressure (ICP) is predicted to have the highest magnitude from a posterior blast wave in comparison with a blast wave from any of the other two directions with same blast intensity. The brain model predicts higher positive pressure at the site proximal to blast wave than that at the distal site. The intracranial pressure wave invariably travels into the posterior fossa and vertebral column, causing high pressures in these regions. The severities of cerebral contusions at different cerebral locations are estimated using an ICP based injury criterion. Von Mises stress prevails in the cortex with a much higher magnitude than in the internal parenchyma. According to an axonal injury criterion based on von Mises stress, axonal injury is not predicted to be a cause of primary brain injury from blasts.     

Explosive Blast Loading on Human 3D Aggregate Minibrains

The effects of primary explosive blast on brain tissue still remain mostly unknown. There are few in vitro models that use real explosives to probe the mechanisms of injury at the cellular level. In this work, 3D aggregates of human brain cells or brain microphysiological system were exposed to military explosives at two different pressures (50 and 100 psi). Results indicate that membrane damage and oxidative stress increased with blast pressure, but cell death remained minimal.     

Mechanisms of central sensitization, neuroimmunology & injury biomechanics in persistent pain: implications for musculoskeletal disorders.

This review will offer an overview of the mechanistic pathways of chronic pain associated with musculoskeletal disorders (MSDs). Traditional electrophysiological pain pathways of these injuries will be reviewed. In addition, recent research efforts in persistent pain have characterized a cascade of neuroimmunologic events in the central nervous system that manifests in pain behaviors and neurochemical nociceptive responses. Physiologic changes in the central nervous system will be covered as they pertain to the interplay of these two areas, and also as they focus on MSDs and injuries. One such injury leading to persistent pain is radiculopathy, which results from nerve root compression or impingement and leads to low back pain. This painful syndrome will be used as an example to provide a context for presenting immune mechanisms of chronic pain and their relationship to injury. Measures of injury biomechanics are presented in the context of the resulting pain responses, including behavioral sensitivity, local structural changes, and cellular and molecular changes in the CNS. Lastly, based on these findings and others, a discussion is provided highlighting areas of future work to help elucidate methods of injury diagnosis and development of therapeutic treatments.     

Prediction of globe rupture caused by primary blast: a finite element analysis

Although a human eye comprises less than 0.1% of the frontal body surface area, injuries to the eye are found to be disproportionally common in survivors of explosions. This study aimed to introduce a Lagrangian–Eulerian coupling model to predict globe rupture resulting from primary blast effect. A finite element model of a human eye was created using Lagrangian mesh. An explosive and its surrounding air domain were modelled using Eulerian mesh. Coupling the two models allowed simulating the blast wave generation, propagation and interaction with the eye. The results showed that the peak overpressures caused by blast wave on the corneal apex are 2080, 932.1 and 487.3 kPa for the victim distances of 0.75, 1.0 and 1.25 m, respectively. Higher stress occurred at the limbus, where the peaks for the three victim distances are 25.5, 14.1 and 6.4 MPa. The overpressure threshold of globe rupture was determined as 2000 kPa in a small-scale explosion. The findings would provide insights into the mechanism of primary blast-induced ocular injuries.     

Modelling human eye under blast loading

Primary blast injury (PBI) is the general term that refers to injuries resulting from the mere interaction of a blast wave with the body. Although few instances of primary ocular blast injury, without a concomitant secondary blast injury from debris, are documented, some experimental studies demonstrate its occurrence. In order to investigate PBI to the eye, a finite element model of the human eye using simple constitutive models was developed. The material parameters were calibrated by a multi-objective optimisation performed on available eye impact test data. The behaviour of the human eye and the dynamics of mechanisms occurring under PBI loading conditions were modelled. For the generation of the blast waves, different combinations of explosive (trinitrotoluene) mass charge and distance from the eye were analysed. An interpretation of the resulting pressure, based on the propagation and reflection of the waves inside the eye bulb and orbit, is proposed. The peculiar geometry of the bony orbit (similar to a frustum cone) can induce a resonance cavity effect and generate a pressure standing wave potentially hurtful for eye tissues.     

Local Government Reform and the Health Services

The shock wave generated by an explosion (“blast wave”) may cause injury in any or all of the following: (1) direct impact on the tissues of variations in environmental pressure; (2) flying glass and other debris set in motion by it; (3) propulsion of the body. Injuries in the first category affect gas-containing organs (ears, lungs and intestines), and acute death is attributed to air forced into the coronary vessels via damaged pulmonary alveoli. It is estimated that overpressure sufficient to cause lung injury may occur up to five miles from a 20-megaton nuclear explosion. The greatest single hazard from blast is, however, flying glass, and serious wounding from this cause is possible up to 12 miles from an explosion of this magnitude.     

Leptin signaling pathways in the central nervous system: interactions between neuropeptide Y and melanocortins.

No other hormone has drawn more attention than leptin in recent studies on the control of appetite, body weight and obesity. This hormone is produced by adipose tissue and enters the brain via a saturable specific transport mechanism. Leptin acts in the hypothalamus to modulate food intake and heat production as well as several other neuroendocrine pathways. The mechanisms through which leptin exerts its central nervous effects are now better understood. Proopiomelanocortin- and neuropeptide Y-containing neurons in the hypothalamus have emerged as potent candidate mediators of leptin action. These two neuropeptides have been shown to exert opposing effects using different pathways. Recently, Cowley et al. (2001) described a new circuit in the regulation of neuronal activity by leptin with an interaction between these two pathways. These data add complexity to the mechanisms by which leptin achieves its effects in the central nervous system, but they also offer potential mechanisms to explain the phenomenon of leptin resistance observed in obesity.     

The polyamine inhibitor alpha-difluoromethylornithine modulates hippocampus-dependent function after single and combined injuries

Exposure to uncontrolled irradiation in a radiologic terrorism scenario, a natural disaster or a nuclear battlefield, will likely be concomitantly superimposed on other types of injury, such as trauma. In the central nervous system, radiation combined injury (RCI) involving irradiation and traumatic brain injury may have a multifaceted character. This may entail cellular and molecular changes that are associated with cognitive performance, including changes in neurogenesis and the expression of the plasticity-related immediate early gene Arc. Because traumatic stimuli initiate a characteristic early increase in polyamine metabolism, we hypothesized that treatment with the polyamine inhibitor alpha-difluoromethylornithine (DFMO) would reduce the adverse effects of single or combined injury on hippocampus structure and function. Hippocampal dependent cognitive impairments were quantified with the Morris water maze and showed that DFMO effectively reversed cognitive impairments after all injuries, particularly traumatic brain injury. Similar results were seen with respect to the expression of Arc protein, but not neurogenesis. Given that polyamines have been found to modulate inflammatory responses in the brain we also assessed the numbers of total and newly born activated microglia, and found reduced numbers of newly born cells. While the mechanisms responsible for the improvement in cognition after DFMO treatment are not yet clear, the present study provides new and compelling data regarding the potential use of DFMO as a potential countermeasure against the adverse effects of single or combined injury.     

Cell-specific and concentration-dependent actions of interleukin-1 in acute brain inflammation

Interleukin (IL)-1 is a pivotal pro-inflammatory cytokine and an important mediator of both acute and chronic central nervous system (CNS) injuries. Despite intense research in CNS IL-1 biology over the past two decades, its precise mechanism of action in inflammatory responses to acute brain disorders remains largely unknown. In particular, much effort has been focussed on using in vitro approaches to better understand the cellular and signalling mechanisms of actions of IL-1, yet some discrepancies in the literature regarding the effects produced by IL-1β in in vitro paradigms of injury still exist, particularly as to whether IL-1 exerts neurotoxic or neuroprotective effects. Here we aim to review the cell-specific and concentration-dependent actions of IL-1 in brain cells, to depict the mechanism by which this cytokine induces neurotoxicity or neuroprotection in acute brain injury.     

Regeneration of the central nervous system-principles from brain regeneration in adult zebrafish

Poor recovery of neuronal functions is one of the most common healthcare challenges for patients with different types of brain injuries and/or neurodegenerative diseases. Therapeutic interventions face two major challenges: (1) How to generate neurons de novo to replenish the neuronal loss caused by injuries or neurodegeneration (restorative neurogenesis) and (2) How to prevent or limit the secondary tissue damage caused by long-term accumulation of glial cells, including microglia, at injury site (glial scar). In contrast to mammals, zebrafish have extensive regenerative capacity in numerous vital organs, including the brain, thus making them a valuable model to improve the existing therapeutic approaches for human brain repair. In response to injuries to the central nervous system (CNS), zebrafish have developed specific mechanisms to promote the recovery of the lost tissue architecture and functionality of the damaged CNS. These mechanisms include the activation of a restorative neurogenic program in a specific set of glial cells (ependymoglia) and the resolution of both the glial scar and inflammation, thus enabling proper neuronal specification and survival. In this review, we discuss the cellular and molecular mechanisms underlying the regenerative ability in the adult zebrafish brain and conclude with the potential applicability of these mechanisms in repair of the mammalian CNS.     

The effects of adrenomedullin in traumatic brain injury

Traumatic brain injury (TBI) is a common cause of death and disability throughout the world. A multifunctional peptide adrenomedullin (AM) has protective effects in the central nervous system. We evaluated AM in an animal model as a therapeutic agent that reduces brain damage after traumatic brain injury. A total of 36 rats was divided into 3 groups as sham, head trauma plus intraperitoneal (ip) saline, and head trauma plus adrenomedullin ip. The diffuse brain injury model of Marmarou et al. was used. Blood samples were taken from all groups at the 1st, 6th and 24th hours for analysis of TNF-α (tumor necrosis factor-α), IL-1β (interleukin-1β) and IL-6 (interleukin-6) levels. At the end of the study (at the 24th hour) a neurological examination was performed and half of the rats were decapitated to obtain blood and tissue samples, the other half were perfused transcardiacally for studying the histopathology of the brain tissue. There were no statistically significant changes in plasma levels of IL-1β, IL-6 and TNF-α relative to the sham group. Also, changes in tissue levels of malonedialdehyde, myeloperoxidase and glutathione were not statistically significant. However, neurological scores and histopathological examinations revealed healing. AM individually exerts neuroprotective effects in animal models of acute brain injury. But the mechanisms of action remain to be assessed.