RESUMO
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)-1ß, 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.
Assuntos
Lesões Encefálicas Traumáticas/imunologia , Imunidade/imunologia , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Receptores de Interleucina-1/antagonistas & inibidores , Retina/imunologia , Percepção Visual/imunologia , Animais , Traumatismos por Explosões/diagnóstico por imagem , Traumatismos por Explosões/tratamento farmacológico , Traumatismos por Explosões/imunologia , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesões Encefálicas Traumáticas/tratamento farmacológico , Eletrorretinografia/métodos , Imunidade/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Retina/diagnóstico por imagem , Retina/efeitos dos fármacos , Tomografia de Coerência Óptica/métodos , Resultado do Tratamento , Percepção Visual/efeitos dos fármacosRESUMO
Traumatic brain injury (TBI) is a leading cause of death and disability that lacks targeted therapies. Successful translation of promising neuroprotective therapies will likely require more precise identification of target populations through greater study of crucial biological factors like age and sex. A growing body of work supports the impact of these factors on response to and recovery from TBI. However, age and sex are understudied in TBI animal models. The first aim of this study was to demonstrate the feasibility of lateral fluid percussion injury (FPI) in juvenile mice as a model of pediatric TBI. Subsequently, we were interested in examining the impact of young age and sex on TBI outcome. After adapting the lateral FPI model to 21-day-old male and female mice, we characterized the molecular, histological, and functional outcomes. Whereas similar tissue injury was observed in male and female juvenile mice exposed to TBI, we observed differences in neuroinflammation and neurobehavioral function. Overall, our findings revealed less acute inflammatory cytokine expression, greater subacute microglial/macrophage accumulation, and greater neurological recovery in juvenile male mice after TBI. Given that ongoing brain development may affect progression of and recovery from TBI, juvenile models are of critical importance. The sex-dependent differences we discovered after FPI support the necessity of also including this biological variable in future TBI studies. Understanding the mechanisms underlying age- and sex-dependent differences may result in the discovery of novel therapeutic targets for TBI.
Assuntos
Lesões Encefálicas/fisiopatologia , Inflamação/fisiopatologia , Macrófagos/metabolismo , Microglia/metabolismo , Recuperação de Função Fisiológica/fisiologia , Animais , Lesões Encefálicas/metabolismo , Citocinas/metabolismo , Feminino , Inflamação/metabolismo , Masculino , Camundongos , Modelos Animais , Fatores SexuaisRESUMO
Homozygous recessive mutations in the PRICKLE1 gene were first described in three consanguineous families with myoclonic epilepsy. Subsequent studies have identified neurological abnormalities in humans and animal models with both heterozygous and homozygous mutations in PRICKLE1 orthologs. We describe a 7-year-old with a novel de novo missense mutation in PRICKLE1 associated with epilepsy, autism spectrum disorder and global developmental delay.