Long‐term consequences of single and multiple mild blast exposure on select physiological parameters and blood‐based biomarkers

Abstract

Mild traumatic brain injury (mTBI), especially when it is repeated (rmTBI), can lead to progressive degenerative diseases and lasting neuropsychiatric abnormalities. To better understand the long-term pathobiological changes in mTBI and rmTBI, we exposed rats to single or repeated (5 total; administered on consecutive days) mild blast overpressure, monitored changes in physiological parameters, and determined the plasma levels of select biomarkers at 42 days post injury by proteomics. We unexpectedly found comparable changes in arterial oxygen saturation levels and heart rates of single-injured (SI) and multiple-injured (MI) rats throughout the observation period. Our analyses indicated lasting oxidative stress, vascular abnormalities, and neuronal and glial cell loss in both injured groups. However, MI rats exhibited a relatively more pronounced increase in the plasma levels of most of the tested markers-particularly those associated with inflammation-albeit the differences between the two injured groups were not statistically significant. Our findings indicate that the frequency of blast exposures is an important determinant of the resulting cumulative damage in rmTBI.

The Temporal Pattern of Changes in Serum Biomarker Levels Reveals Complex and Dynamically Changing Pathologies after Exposure to a Single Low-Intensity Blast in Mice

“…Moreover, mbTBI, especially when repeated, could significantly increase the probability of late onset neurodegenerative conditions, such as chronic traumatic encephalopathy (CTE) (9, 10). Finally, blast interacting with the entire body and not only with the head, induces complex co-occurring systemic, local, and cerebral responses to injury (11–14). Thus, the neurological deficits that develop after blast exposure(s) are resulted not only from the brain damage caused via head-blast interaction but also from multiple, synergistically acting injury mechanisms.…”

Blast induced neurotrauma causes overpressure dependent changes to the DNA methylation equilibrium

“…Oxidative stress may be another factor in the dynamic methylation levels following BOP exposure. Oxidative stress is a well-documented consequence of BINT and TBI [8][9][10]13,14,30] and has been shown to effect DNA methylation [31]. Oxidative stress and reactive oxygen species (ROS) accumulation can lead to DNA damage which prevents the methylation of nucleotides [32].…”

Combined Effects of Primary and Tertiary Blast on Rat Brain: Characterization of a Model of Blast-induced Mild Traumatic Brain Injury

“…All animals underwent a 5 day acclimation and handling period and were later assigned to the following groups: naïve, single sham (SS), single-injured (SI), multiple sham (MS), and multiple-injured (MI) as described earlier 36,49 . Rat numbers in the early and late termination groups were: (N 5 30; naïve 5 3, SS 5 6, SI 5 7, MS 5 6, MI 5 8) and (N 5 30; naïve 5 3, SS 5 6, SI 5 7, MS 5 6, MI 5 8), respectively.…”

“…A subset of animals from each experiment [(2 h termination: n 5 11; SS 5 2, SI 5 3, MS 5 3, MI 5 3) and (42 day termination: n 5 16; SS 5 4, SI 5 4, MS 5 4, MI 5 4)] was used for MRI/DTI analyses; all other animals were used for proteomics as described earlier 36,49 . Rats were deeply anesthetized with isoflurane inhalant until a tail pinch produced no reflex movement, then transcardially perfused with cold phosphate-buffered saline (PBS) followed by a 4% paraformaldehyde in 1x PBS solution.…”

“…The abovementioned caveats underline the importance of combining objective and clinically relevant outcome measures in experimental TBI to validate and correlate findings, to enable more direct comparisons of pathologies observed in animal and in clinical TBI research, and to enable the development of sensitive and specific diagnostics for mbTBI Methods Animals and housing conditions. A total of 60 male Sprague Dawley rats (weight at arrival: 245-265 g) (Charles River Laboratories, Wilmington, MA) were used in the original experiments 36,49 . All animals were housed in standard rat cages with a built-in filter in a reverse 12-h light 12-h dark cycle with food and water ad lib.…”