Abstract
The aim of this study was to evaluate the neuroprotective efficacy of the inert gas xenon as a treatment for patients with blast-induced traumatic brain injury in an in vitro laboratory model. We developed a novel blast traumatic brain injury model using C57BL/6N mouse organotypic hippocampal brain-slice cultures exposed to a single shockwave, with the resulting injury quantified using propidium iodide fluorescence. A shock tube blast generator was used to simulate open field explosive blast shockwaves, modeled by the Friedlander waveform. Exposure to blast shockwave resulted in significant (p < 0.01) injury that increased with peak-overpressure and impulse of the shockwave, and which exhibited a secondary injury development up to 72 h after trauma. Blast-induced propidium iodide fluorescence overlapped with cleaved caspase-3 immunofluorescence, indicating that shock-wave–induced cell death involves apoptosis. Xenon (50% atm) applied 1 h after blast exposure reduced injury 24 h (p < 0.01), 48 h (p < 0.05), and 72 h (p < 0.001) later, compared with untreated control injury. Xenon-treated injured slices were not significantly different from uninjured sham slices at 24 h and 72 h. We demonstrate for the first time that xenon treatment after blast traumatic brain injury reduces initial injury and prevents subsequent injury development in vitro. Our findings support the idea that xenon may be a potential first-line treatment for those with blast-induced traumatic brain injury.
Highlights
Traumatic brain injury (TBI) is a leading cause of death and disability in both military and civilian populations,[1,2,3] but there are, as yet, no effective treatments targeting injury development
The Organotypic hippocampal slice cultures (OHSCs) exposed to blast-injury exhibited increased propidium iodide (PI) fluorescence, compared with identically treated sham slices (Fig. 2C i, ii)
We have shown in an animal model of blunt TBI that xenon treatment for only three hours results in significant neuroprotection.[31]
Summary
Traumatic brain injury (TBI) is a leading cause of death and disability in both military and civilian populations,[1,2,3] but there are, as yet, no effective treatments targeting injury development. Blast-TBI has been called a ‘‘signature injury’’ of recent military operations in Iraq and Afghanistan.[2,3] While blunt and penetrating TBI injury have been studied extensively, blast-TBI is much less well understood but is being recognized as having a unique pathophysiology.[4] The prevalence of blast-injury in recent returning veteran populations[5,6] has prompted research into blast-TBI. Despite the increasing research focus on blast-TBI pathophysiology, there are no clinically proven treatments to prevent or limit ongoing brain injury after blast-TBI. To date there have been few pre-clinical studies evaluating potential treatments or reporting improved outcomes after blast-TBI.[8,10,11] There is an urgent need for treatments aimed at mitigating the neurological and cognitive deficits caused by blast-TBI and promoting a more rapid and complete recovery
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