S. Svetlov, K. Wang, S. Murphy, F. Kobeissy, P. Vandevord
Keywords: hypersonic/supersonic shock, brain repair, genomic signatures, blood biomarkers, RBC
Summary:Combat operations using hypersonic or supersonic weapon with or without nuclear charge have raised necessity to develop medical countermeasures and mitigation strategy and increase personnel resilience. The hypersonic shock waves produce micro-radiation emission from the surface, overpressure impulse, thermal exposure and the sound coming behind. Health effects of repeated non-lethal hypersonic shock accompanied by radiation have not been established, particularly long-term CNS sequelae and recovery. Hence, no medical tools are available to assess and mitigate brain disorders in survivors, monitor and enhance personnel resilience. The main obstacle is a lack of experimental framework to reproduce effects of hypersonic shock waves on higher organisms, including non-human primates, and relevant biomarkers of brain recovery. Molecular mechanisms and biomarkers of neural regeneration and rehabilitation from combat related exposures remain to be elucidated. Important question addressed is whether hypersonic shock wave exposures produce changes in gene expression and regulation in the brain, and if peripheral red blood cells may serve as a ‘mirror’ indicating long-term remodeling in the brain reflecting neural regeneration and recovery. The presence of posttranscriptional genomic material (mRNA and miRNA) in RBC may reflect asymmetric RNA distribution process between brain, BBB cells and circulation. RBC genomics may provide insight in our knowledge of how brain communicates to periphery and vice-versa in normal and injurious conditions via exchanging genomic information. Hence, RBC RNA profile can serve as dynamic biomarkers reflecting neural recovery and patient rehabilitation. In this study, we evaluated genomic pathways critical for neurorepair following shock wave of ~3 Mach supersonic speed with moderate power impulse of 165 psi/msec and analyzed using Neurosystems Biology approach presenting a graphic interaction map. We assessed impaired vascular reactions, systemic responses, neuroinflammation, BBB disruption and enhancement of endothelial permeability, recruitment of immune cells and activation of brain-resident glial cells. Markers of vascular/endothelial and systemic inflammation TNF-a, IL-1-a/b, IL-10, neuroendocrine peptide Orexin A, and VEGF receptor Neuropilin-2 (NRP-2) along with neurotrophic growth factors beta-NGF, CNTF and were increased in serum in acute 24 hours and subacute 7 days post-exposure. Novel genomic pathways that shown to play a role in neurorepair in cultured cells were changed after shock wave exposures in the brain: ASCL1/Mash1, Activin receptor-like kinase 7 (neuronal expression) and SRY-box containing genes are important in neuronal survival and were significantly up-regulated after blast exposure in our study. Important, expression of neural precursor cell expressed developmentally down-regulated gene 4A (NEDD4A), Dihydropyrimidinase-like 3 (CRMP-4) and ROBO1 were significantly down regulated after shock wave treatment compared respective controls. Conclusion: We demonstrate changes in gene expression and regulation of neurorepair in the brain after shock insult and compared to the mechanical neurotrauma. Data reveal disparities as well as some overlaps in the genomic repertoire related to neural regeneration and repair. Novel approaches to the development of prognostic tests to assess neural regeneration and strategies to enhance brain recovery will be presented.