Abstract
The purpose of this study was to characterize acute changes in inflammatory pathways in the mouse eye after blast-mediated traumatic brain injury (bTBI) and to determine whether modulation of these pathways could protect the structure and function of retinal ganglion cells (RGC). The bTBI was induced in C57BL/6J male mice by exposure to three 20 psi blast waves directed toward the head with the body shielded, with an inter-blast interval of one hour. Acute cytokine expression in retinal tissue was measured through reverse transcription-quantitative polymerase chain reaction (RT-qPCR) four hours post-blast. Increased retinal expression of interleukin (lL)-1β, IL-1α, IL-6, and tumor necrosis factor (TNF)α was observed in bTBI mice exposed to blast when compared with shams, which was associated with activation of microglia and macroglia reactivity, assessed via immunohistochemistry with ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein, respectively, one week post-blast. Blockade of the IL-1 pathway was accomplished using anakinra, an IL-1RI antagonist, administered intra-peritoneally for one week before injury and continuing for three weeks post-injury. Retinal function and RGC layer thickness were evaluated four weeks post-injury using pattern electroretinogram (PERG) and optical coherence tomography (OCT), respectively. After bTBI, anakinra treatment resulted in a preservation of RGC function and RGC structure when compared with saline treated bTBI mice. Optic nerve integrity analysis demonstrated a trend of decreased damage suggesting that IL-1 blockade also prevents axonal damage after blast. Blast exposure results in increased retinal inflammation including upregulation of pro-inflammatory cytokines and activation of resident microglia and macroglia. This may explain partially the RGC loss we observed in this model, as blockade of the acute inflammatory response after injury with the IL-1R1 antagonist anakinra resulted in preservation of RGC function and RGC layer thickness.
Highlights
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, which results in enormous social and economic costs
Because robust neuroinflammation occurs in the brain after several types of TBI,[15] we first examined the messenger Ribonucleic acid (RNA) (mRNA) levels of classic proinflammatory cytokines in the retina and brain after blast-related injuries causing TBI (bTBI)
At 4 h post-repeated bTBI, there was an acute increase in retinal inflammatory cytokine mRNA when normalized to sham values, with increased expression of IL-1b ( p < 0.0001), IL-1a ( p = 0.003), TNFa ( p < 0.0001), and IL-6 ( p < 0.0001) in the ipsilateral retinas of blast-injured mice (Fig. 7A)
Summary
Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, which results in enormous social and economic costs. Because of the use of improvised explosive devices in 21st century military conflicts, the number of blast-related injuries causing TBI (bTBI) has increased dramatically in both military personnel and civilians, while blast-related deaths have decreased because of enhanced protective equipment.[1,2] there are no effective pharmacological therapies to prevent neuronal loss after blast, and treatment is limited to supportive care. The retina is a central nervous system (CNS) tissue vulnerable to injuries affecting the brain.[3] This is true in the setting of bTBI because the eye is exposed to the primary blast wave. Many military personnel and civilians who have bTBI report
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