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

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.

Blast Wave Exposure Impairs Memory and Decreases Axon Initial Segment Length

“…While some studies of blast-induced brain injury have reported gliosis and axon degeneration, 45 we did not observe any of these in our model. Instead, we measured a significant decrease in AIS length.…”

“…For example, the rise time of the blast overpressure is longer than that of a blast wave generated by an explosion, (although a wide range of blast overpressure amplitudes and durations have been used). [42][43][44][45] It is not known, however, which component(s) of the blast wave causes mTBI (the rapid change in pressure, the amplitude of the pressure wave, or the duration of the pressure wave). Nevertheless, it is important to emphasize that the model used here produced symptoms consistent with a mTBI including memory impairment.…”

Early Characterization of Blast-related Heterotopic Ossification in a Rat Model

“…Rats were anesthetized with isoflurane (2%-5%) and received full-body blast overpressure (120 ± 7 kPa) exposure, without any shielding to the blast wave, through a pneumatically driven shock tube [1,4,29]. Preoperative buprenorphine (0.05 mg/kg) was then administered through intraperitoneal injection and a reproducible comminuted fracture of the right femur was performed using a drop weight apparatus from a height of 88 cm.…”

Screening of Biochemical and Molecular Mechanisms of Secondary Injury and Repair in the Brain after Experimental Blast-Induced Traumatic Brain Injury in Rats

“…Increase in gene expression of astrocyte markers at 24 h mirrors other reports using proteomics or immunohistochemistry. 31,35,36 In the CCI model in rats, GFAP and vimentin, assessed by two-dimensional (2D) gel, also showed large increases in the hippocampus. 37 Astrocytes play a neuroprotectant after CCI 38 ; however, their role in blast TBI is undefined.…”