Neuro-glial and systemic mechanisms of pathological responses in rat models of primary blast overpressure compared to “composite” blast

Stanislav I. Svetlov

doi:10.3389/fneur.2012.00015

Abstract

A number of experimental models of blast brain injury have been implemented in rodents and larger animals. However, the variety of blast sources and the complexity of blast wave biophysics have made data on injury mechanisms and biomarkers difficult to analyze and compare. Recently, we showed the importance of rat position toward blast generated by an external shock tube. In this study, we further characterized blast producing moderate traumatic brain injury and defined “composite” blast and primary blast exposure set-ups. Schlieren optics visualized interaction between the head and a shock wave generated by external shock tube, revealing strong head acceleration upon positioning the rat on-axis with the shock tube (composite blast), but negligible skull movement upon peak overpressure exposure off-axis (primary blast). Brain injury signatures of a primary blast hitting the frontal head were assessed and compared to damage produced by composite blast. Low to negligible levels of neurodegeneration were found following primary blast compared to composite blast by silver staining. However, persistent gliosis in hippocampus and accumulation of GFAP/CNPase in circulation was detected after both primary and composite blast. Also, markers of vascular/endothelial inflammation integrin alpha/beta, soluble intercellular adhesion molecule-1, and L-selectin along with neurotrophic factor nerve growth factor-beta were increased in serum within 6 h post-blasts and persisted for 7 days thereafter. In contrast, systemic IL-1, IL-10, fractalkine, neuroendocrine peptide Orexin A, and VEGF receptor Neuropilin-2 (NRP-2) were raised predominantly after primary blast exposure. In conclusion, biomarkers of major pathological pathways were elevated at all blast set-ups. The most significant and persistent changes in neuro-glial markers were found after composite blast, while primary blast instigated prominent systemic cytokine/chemokine, Orexin A, and Neuropilin-2 release, particularly when primary blast impacted rats with unprotected body.

Highlights

The nature of twenty-first century warfare has led to a significant increase in human exposure to blast overpressure (OP) impulses, which result in a complex of neuro-somatic disorders, including traumatic brain injury (TBI)
For every blast-related fatality, many more soldiers suffer multiple, low level non-lethal blast exposures. This often leads to mild traumatic brain injury, which is rarely recognized in a timely manner and has become a signature injury of the Iraq and Afghanistan conflicts (Warden, 2006; Jones et al, 2007; Terrio et al, 2009)
“COMPOSITE” BLAST EXPOSURE Our shock tube was designed and built to model a freely expanding blast wave as generated by a typical explosion. Both static and www.frontiersin.org dynamic pressures were measured as functions of angle and radial distance from shock tube exit using piezoelectric blast pressure transducers positioned at the target (Figure 1C)

Summary

Introduction

The nature of twenty-first century warfare has led to a significant increase in human exposure to blast overpressure (OP) impulses, which result in a complex of neuro-somatic disorders, including traumatic brain injury (TBI). For every blast-related fatality, many more soldiers suffer multiple, low level non-lethal blast exposures. This often leads to mild traumatic brain injury (mTBI), which is rarely recognized in a timely manner and has become a signature injury of the Iraq and Afghanistan conflicts (Warden, 2006; Jones et al, 2007; Terrio et al, 2009). Even mild and moderate brain injuries can produce significant deficits and, when repeated, can lead to sustained neuro-somatic damage and neurodegeneration (Cernak and Noble-Haeusslein, 2010).

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