RESUMEN
BACKGROUND: Neuregulin-1 (NRG-1) has been shown to act as a neuroprotectant in animal models of nerve agent intoxication and other acute brain injuries. We recently demonstrated that NRG-1 blocked delayed neuronal death in rats intoxicated with the organophosphate (OP) neurotoxin diisopropylflurophosphate (DFP). It has been proposed that inflammatory mediators are involved in the pathogenesis of OP neurotoxin-mediated brain damage. METHODS: We examined the influence of NRG-1 on inflammatory responses in the rat brain following DFP intoxication. Microglial activation was determined by immunohistchemistry using anti-CD11b and anti-ED1 antibodies. Gene expression profiling was performed with brain tissues using Affymetrix gene arrays and analyzed using the Ingenuity Pathway Analysis software. Cytokine mRNA levels following DFP and NRG-1 treatment was validated by real-time reverse transcription polymerase chain reaction (RT-PCR). RESULTS: DFP administration resulted in microglial activation in multiple brain regions, and this response was suppressed by treatment with NRG-1. Using microarray gene expression profiling, we observed that DFP increased mRNA levels of approximately 1,300 genes in the hippocampus 24 h after administration. NRG-1 treatment suppressed by 50% or more a small fraction of DFP-induced genes, which were primarily associated with inflammatory responses. Real-time RT-PCR confirmed that the mRNAs for pro-inflammatory cytokines interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) were significantly increased following DFP exposure and that NRG-1 significantly attenuated this transcriptional response. In contrast, tumor necrosis factor α (TNFα) transcript levels were unchanged in both DFP and DFP + NRG-1 treated brains relative to controls. CONCLUSION: Neuroprotection by NRG-1 against OP neurotoxicity is associated with the suppression of pro-inflammatory responses in brain microglia. These findings provide new insight regarding the molecular mechanisms involved in the neuroprotective role of NRG-1 in acute brain injuries.
Asunto(s)
Inhibidores de la Colinesterasa/toxicidad , Inhibidores de la Colinesterasa/uso terapéutico , Encefalitis/inducido químicamente , Isoflurofato/toxicidad , Neurregulina-1/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Animales , Encéfalo/patología , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Inyecciones Intraarteriales , Masculino , Microglía/efectos de los fármacos , Microglía/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero , Ratas , Ratas Sprague-DawleyRESUMEN
Microarray analysis has been used to understand how gene regulation plays a critical role in neuronal injury, survival and repair following ischemic stroke. To identify the transcriptional regulatory elements responsible for ischemia-induced gene expression, we examined gene expression profiles of rat brains following focal ischemia and performed computational analysis of consensus transcription factor binding sites (TFBS) in the genes of the dataset. In this study, rats were sacrificed 24 h after middle cerebral artery occlusion (MCAO) stroke and gene transcription in brain tissues following ischemia/reperfusion was examined using Affymetrix GeneChip technology. The CONserved transcription FACtor binding site (CONFAC) software package was used to identify over-represented TFBS in the upstream promoter regions of ischemia-induced genes compared to control datasets. CONFAC identified 12 TFBS that were statistically over-represented from our dataset of ischemia-induced genes, including three members of the Ets-1 family of transcription factors (TFs). Microarray results showed that mRNA for Ets-1 was increased following tMCAO but not pMCAO. Immunohistochemical analysis of Ets-1 protein in rat brains following MCAO showed that Ets-1 was highly expressed in neurons in the brain of sham control animals. Ets-1 protein expression was virtually abolished in injured neurons of the ischemic brain but was unchanged in peri-infarct brain areas. These data indicate that TFs, including Ets-1, may influence neuronal injury following ischemia. These findings could provide important insights into the mechanisms that lead to brain injury and could provide avenues for the development of novel therapies.
Asunto(s)
Encéfalo , Regulación de la Expresión Génica/genética , Ataque Isquémico Transitorio/genética , Proteína Proto-Oncogénica c-ets-1/genética , Animales , Sitios de Unión/genética , Inmunohistoquímica , Infarto de la Arteria Cerebral Media/genética , Flujometría por Láser-Doppler , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Regiones Promotoras Genéticas/genética , Proteína Proto-Oncogénica c-ets-1/biosíntesis , Ratas , Ratas Sprague-Dawley , TranscriptomaRESUMEN
We describe the case of a 59-year-old woman who presented with progressive bilateral vestibular hypofunction and who was found to have bilateral granulomatous mass lesions of the mesial temporal lobe. Initially, her condition stabilized neurologically with corticosteroids, but a diagnosis of neurosarcoidosis was delayed because of the unusual presentation and persistently normal chest imaging results and serum angiotensin-converting enzyme (ACE) levels. Approximately 1 year after her initial presentation, the patient died of complications of a myocardial infarction and pulmonary embolism. Sarcoidosis should be considered in the differential diagnosis of idiopathic bilateral vestibular hypofunction even if the chest imaging and serum ACE levels are normal, particularly when there is evidence of a multisystem process.