Repeated Low-Level Blast Acutely Alters Brain Cytokines, Neurovascular Proteins, Mechanotransduction, and Neurodegenerative Markers in a Rat Model.

Lanier Heyburn,Joseph B Long,Samantha Goodrich,Peethambaran Arun,Venkatasivasai Sujith Sajja,Donna M Wilder,Rodrigo Urioste,Rania Abutarboush,Andrew Batuure,Stephen T Ahlers,Jaimena Wheel

doi:10.3389/fncel.2021.636707

Abstract

Exposure to the repeated low-level blast overpressure (BOP) periodically experienced by military personnel in operational and training environments can lead to deficits in behavior and cognition. While these low-intensity blasts do not cause overt changes acutely, repeated exposures may lead to cumulative effects in the brain that include acute inflammation, vascular disruption, and other molecular changes, which may eventually contribute to neurodegenerative processes. To identify these acute changes in the brain following repeated BOP, an advanced blast simulator was used to expose rats to 8.5 or 10 psi BOP once per day for 14 days. At 24 h after the final BOP, brain tissue was collected and analyzed for inflammatory markers, astrogliosis (GFAP), tight junction proteins (claudin-5 and occludin), and neurodegeneration-related proteins (Aβ40/42, pTau, TDP-43). After repeated exposure to 8.5 psi BOP, the change in cytokine profile was relatively modest compared to the changes observed following 10 psi BOP, which included a significant reduction in several inflammatory markers. Reduction in the tight junction protein occludin was observed in both groups when compared to controls, suggesting cerebrovascular disruption. While repeated exposure to 8.5 psi BOP led to a reduction in the Alzheimer’s disease (AD)-related proteins amyloid-β (Aβ)40 and Aβ42, these changes were not observed in the 10 psi group, which had a significant reduction in phosphorylated tau. Finally, repeated 10 psi BOP exposures led to an increase in GFAP, indicating alterations in astrocytes, and an increase in the mechanosensitive ion channel receptor protein, Piezo2, which may increase brain sensitivity to injury from pressure changes from BOP exposure. Overall, cumulative effects of repeated low-level BOP may increase the vulnerability to injury of the brain by disrupting neurovascular architecture, which may lead to downstream deleterious effects on behavior and cognition.

Highlights

Blast overpressure (BOP) exposure has become a subject of increasing concern in the Department of Defense due to increased use of breaching operations and heavy weapons systems in both combat and in training, in which military personnel are exposed to repeated low-level blast overpressure (BOP) (Tate et al, 2013)
All animal experiments were conducted under an approved animal use protocol in an AAALACi accredited facility in compliance with the Animal Welfare Act and other federal statutes and regulations relating to animals and experiments involving animals, with strict adherence to principles stated in the Guide for the Care and Use of Laboratory Animals, NRC Publication, 2011 edition
We found that vascular endothelial growth factor (VEGF) and the tight junction proteins claudin-5 and occludin are decreased following repeated low-level BOP exposure, with a significant reduction in occludin after repeated 8.5 psi BOP and a significant reduction in VEGF after repeated 10 psi BOP exposure (Figure 3)

Summary

Introduction

Blast and impact injuries are biomechanically different, some neurological symptoms of moderately-severe BOP exposure are similar to those in impact traumatic brain injury (TBI) but have been shown to have different pathophysiological profiles (Shively et al, 2016; Yamamoto et al, 2018). Tight junction proteins such as claudin-5 and occludin are altered in Warfighters’ blood-based clinical assessments following repeated BOP exposure (Duckworth, 2018). Glial fibrillary acidic protein (GFAP), an astrocytic marker, and vascular endothelial growth factor (VEGF), a mediator of angiogenesis in the brain, were shown to be affected following BOP exposure (Sajja et al, 2012a; Kamnaksh et al, 2014; Duckworth, 2018; Eonta et al, 2019). The breakdown of the border separating cerebral blood flow from the brain parenchyma leaves the brain susceptible to infiltrating cells and brain-toxic elements that can promote neuroinflammation and cell death (Shetty et al, 2014)

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