Elsevier

NeuroImage

Volume 54, Supplement 1, January 2011, Pages S89-S97
NeuroImage

Mechanisms of blast induced brain injuries, experimental studies in rats

https://doi.org/10.1016/j.neuroimage.2010.05.031Get rights and content

Abstract

Traumatic brain injuries (TBI) potentially induced by blast waves from detonations result in significant diagnostic problems. It may be assumed that several mechanisms contribute to the injury. This study is an attempt to characterize the presumed components of the blast induced TBI. Our experimental models include a blast tube in which an anesthetized rat can be exposed to controlled detonations of explosives that result in a pressure wave with a magnitude between 130 and 260 kPa. In this model, the animal is fixed with a metal net to avoid head acceleration forces. The second model is a controlled penetration of a 2 mm thick needle. In the third model the animal is subjected to a high-speed sagittal rotation angular acceleration. Immunohistochemical labeling for amyloid precursor protein revealed signs of diffuse axonal injury (DAI) in the penetration and rotation models. Signs of punctuate inflammation were observed after focal and rotation injury. Exposure in the blast tube did not induce DAI or detectable cell death, but functional changes. Affymetrix Gene arrays showed changes in the expression in a large number of gene families including cell death, inflammation and neurotransmitters in the hippocampus after both acceleration and penetration injuries. Exposure to the primary blast wave induced limited shifts in gene expression in the hippocampus. The most interesting findings were a downregulation of genes involved in neurogenesis and synaptic transmission. These experiments indicate that rotational acceleration may be a critical factor for DAI and other acute changes after blast TBI. The further exploration of the mechanisms of blast TBI will have to include a search for long-term effects.

Introduction

The use of improvised explosive devices (IED) in terrorist attacks has resulted in a new spectrum of traumatic brain injuries (TBI) (Warden, 2006, Jaffee and Meyer, 2009, Ling et al., 2009). The injuries may occur as a direct result of the supersonic blast wave which induces rapid changes in atmospheric pressure (primary blast injury), by impact of small fragments or larger objects that are put in motion by the blast (secondary blast injury) and when victims are thrown by the blast (tertiary blast injury). It can be assumed that detonations can generate different effects in different parts of the body. Lethal injuries may develop as a result of bleeding or rupturing when air-containing organs such as the lungs and the gastro-intestinal tract are subjected to blast trauma (Clemedson, 1956, Mayorga, 1997). The possible effect of blast related trauma to the nervous system can be much more difficult to evaluate, due to the complex structure and functioning of the brain. Mild injuries, without focal manifestation, seem to be an especially enigmatic type of blast related brain injury and can occur with or without posttraumatic stress disorder (PTSD) (Clemedson, 1956, Cernak et al., 1999, Gaylord et al., 2008, Hoge et al., 2008, Brenner et al., 2009).

It may be assumed that the primary blast overpressure alone could result in a spectrum of TBI ranging from mild to severe. The effects of a blast wave appear to be difficult to predict, due to the complex propagation of pressure waves through the walls of the cranium, the cerebrospinal fluid and the brain or indirect propagation in the vascular system from other regions of the body (Cernak and Noble-Haeusslein, 2010). If the brain is subjected to a rapid acceleration from a secondary or tertiary blast effects, different parts of the brain may be accelerated at different relative rates, resulting in diffuse injuries from stretching and shearing forces. Focal impact during a secondary blast can result in local tissue destruction as well as diffuse injuries when the local overpressure is transmitted to other regions. In order to provide a better understanding of the relative importance of such factors we have used three different models to examine the effects of blast related TBI in the brain of adult rats. These three experimental models include a blast tube in which an anesthetized experimental rat can be exposed to controlled detonations of explosives that result in a pressure wave with a peak magnitude between 130 and 260 kPa (Clemedson and Criborn, 1955, Säljö et al., 2000, Risling et al., 2002b). Exposure to pressure waves above 260 kPa usually results in lethal bleedings from the airways. In this model, the animal is fixed with a metal net to avoid acceleration forces and no emissions of metal fragments occur from the detonation. The second model is a controlled penetration of a 2 mm thick needle shaped object, which is accelerated with a bullet from an air gun (Risling et al., 2004). In the third model the animal is subjected to a high-speed sagittal rotation acceleration. A lever that is firmly attached to the exposed skull bone is impacted with a bullet from an air gun and creates an acceleration of short duration and a rotational axis close to the base of the brain (Davidsson et al., 2009). After 2 h up to 3 weeks the animals were sacrificed and the brain was removed for gene expression analysis or microscopical examination. A more detailed description of morphological changes for each of the models is provided in other studies focusing on timetables for cell death, gliosis, edema, and inflammation as well as diffuse axonal injuries (DAI). In this study, we provide comparison on gene expression findings. The results show that each of the three types result in a distinct pattern of changes. These data can hopefully guide and facilitate the development of strategies for the examination of clinical cases of blast induced TBI.

Section snippets

Materials and methods

All animal experiments were approved by the local ethics committee in Stockholm or Umeå. Adult Sprague–Dawley rats were anesthetized by isoflurane inhalation or by intra-abdominal injections injection of a 2.4 ml/kg of a mixture of 1 ml Dormicum® (5 mg/ml Midazolam, Roche), 1 ml Hypnorm® (Janssen) and 2 ml of distilled water. Thereafter the subjects were given 0.2 ml/kg intra-muscular injections every 0.5 h.

Results

Rotation/acceleration injury induced axonal changes that could be revealed by labeling for APP by 2 h after the injury (Davidsson et al., 2009) (Fig. 2A). For the cerebrum the typical location of axonal injury was at the border between grey and white matter and in the corpus callosum. The brain stem and cerebellum have not been analyzed in detail at present. A rapid and intense induction of cyclooxygenase 2 (COX2) mRNA could be observed in the dentate gyrus within 3 h after the injury. This is in

Discussion

Our data indicate that the primary blast model (without acceleration movements) represents a mild injury state. No structural damage was observed in the brain, although we have observed cell death in the cochlea in the same exposed animals and published gene array data on the regulation of apoptosis genes in this end-organ (Kirkegaard et al., 2006, Murai et al., 2008). A previous study using MRI (4.7 Tesla) after the exposure to a similar blast did not indicate any significant changes in brain

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Role of funding source

Funding for the project has been provided by Karolinska institutet and the Swedish Defense.

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