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1.
Exp Neurol ; 335: 113516, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33172833

RESUMO

The degree of brain injury is the governing factor for the magnitude of the patient's psycho- and physiological deficits post-injury, and the associated long-term consequences. The present scaling method used to segregate the patients among mild, moderate and severe phases of traumatic brain injury (TBI) has major limitations; however, a more continuous stratification of TBI is still elusive. With the anticipation that differentiating molecular markers could be the backbone of a robust method to triage TBI, we used a modified closed-head injury (CHI) Marmarou model with two impact heights (IH). By definition, IH directly correlates with the impact force causing TBI. In our modified CHI model, the rat skull was fitted with a helmet to permit a diffuse axonal injury. With the frontal cortex as the focal point of injury, the adjacent brain regions (hippocampus, HC and cerebellum, CB) were susceptible to diffuse secondary shock injury. At 8 days post injury (po.i.), rats impacted by 120 cm IH (IH120) took a longer time to find an escape route in the Barnes maze as compared to those impacted by 100 cm IH (IH100). Using a time-resolved interrogation of the transcriptomic landscape of HC and CB tissues, we mined those genes that altered their regulations in correlation with the variable IHs. At 14 days po.i., when all rats demonstrated nearly normal visuomotor performance, the bio-functional analysis suggested an advanced healing mechanism in the HC of IH100 group. In contrast, the HC of IH120 group displayed a delayed healing with evidence of active cell death networks. Combining whole genome rat microarrays with behavioral analysis provided the insight of neuroprotective signals that could be the foundation of the next generation triage for TBI patients.


Assuntos
Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/patologia , Cerebelo/patologia , Hipocampo/patologia , Transcriptoma , Animais , Peso Corporal , Lesões Encefálicas Traumáticas/psicologia , Corticosterona/sangue , Lesão Axonal Difusa/genética , Lesão Axonal Difusa/patologia , Lobo Frontal/lesões , Traumatismos Cranianos Fechados/genética , Traumatismos Cranianos Fechados/patologia , Masculino , Aprendizagem em Labirinto , Análise em Microsséries , Desempenho Psicomotor , Ratos , Ratos Wistar , Recuperação de Função Fisiológica
2.
Int J Mol Sci ; 21(18)2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32967238

RESUMO

Following traumatic brain injury (TBI), the time window during which secondary injuries develop provides a window for therapeutic interventions. During this time, many TBI victims undergo exposure to hyperoxia and anesthetics. We investigated the effects of genetic background on the interaction of oxygen and volatile general anesthetics with brain pathophysiology after closed-head TBI in the fruit fly Drosophila melanogaster. To test whether sevoflurane shares genetic risk factors for mortality with isoflurane and whether locomotion is affected similarly to mortality, we used a device that generates acceleration-deceleration forces to induce TBI in ten inbred fly lines. After TBI, we exposed flies to hyperoxia alone or in combination with isoflurane or sevoflurane and quantified mortality and locomotion 24 and 48 h after TBI. Modulation of TBI-induced mortality and locomotor impairment by hyperoxia with or without anesthetics varied among fly strains and among combinations of agents. Resistance to increased mortality from hyperoxic isoflurane predicted resistance to increased mortality from hyperoxic sevoflurane but did not predict the degree of locomotion impairment under any condition. These findings are important because they demonstrate that, in the context of TBI, genetic background determines the latent toxic potentials of oxygen and anesthetics.


Assuntos
Anestésicos Inalatórios/farmacologia , Patrimônio Genético , Traumatismos Cranianos Fechados , Hiperóxia , Isoflurano/farmacologia , Sevoflurano/farmacologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Lesões Encefálicas Traumáticas/tratamento farmacológico , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Modelos Animais de Doenças , Drosophila melanogaster , Traumatismos Cranianos Fechados/tratamento farmacológico , Traumatismos Cranianos Fechados/genética , Traumatismos Cranianos Fechados/metabolismo , Traumatismos Cranianos Fechados/patologia , Humanos , Hiperóxia/tratamento farmacológico , Hiperóxia/genética , Hiperóxia/metabolismo , Hiperóxia/patologia , Consumo de Oxigênio/efeitos dos fármacos
3.
Exp Neurol ; 327: 113207, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31962129

RESUMO

One of the consistent pathologies associated with both clinical and experimental traumatic brain injury is axonal injury, especially following mild traumatic brain injury (or concussive injury). Several lines of experimental evidence have demonstrated a role for NAD+ metabolism in axonal degeneration. One of the enzymes that metabolizes NAD+ in axons is Sarm1 (Sterile Alpha and TIR Motif Containing 1), and its activity is thought to play a key role in axonal degeneration. Using a Sarm1 knock-out mouse, we examined if loss of Sarm1 offers axonal injury protection and improves cognitive outcome after repeated mild closed head injury (rmCHI). Our results indicate that rmCHI caused white matter damage that can be observed in the corpus callosum, cingulum bundle, alveus of the hippocampus, and fimbria of the fornix of wild-type mice. These pathological changes were markedly reduced in injured Sarm1-/- mice. Interestingly, the activation of astrocytes and microglia was also attenuated in the areas with white matter damage, suggesting reduced inflammation. Associated with these improved pathological outcomes, injured Sarm1-/- mice performed significantly better in both motor and cognitive tasks. Taken together, our results suggest that strategies aimed at inhibiting Sarm1 and/or restoring NAD+ levels in injured axons may have therapeutic utility.


Assuntos
Proteínas do Domínio Armadillo/genética , Axônios/metabolismo , Encéfalo/metabolismo , Cognição/fisiologia , Proteínas do Citoesqueleto/genética , Traumatismos Cranianos Fechados/genética , Substância Branca/metabolismo , Animais , Proteínas do Domínio Armadillo/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Axônios/patologia , Encéfalo/patologia , Proteínas do Citoesqueleto/metabolismo , Traumatismos Cranianos Fechados/metabolismo , Traumatismos Cranianos Fechados/patologia , Masculino , Camundongos , Camundongos Knockout , Microglia/metabolismo , Microglia/patologia , Atividade Motora/fisiologia , Neurônios/metabolismo , Neurônios/patologia , Reconhecimento Psicológico/fisiologia , Substância Branca/patologia
4.
Neuromolecular Med ; 21(2): 170-181, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30900118

RESUMO

Mild traumatic brain injury (mTBI) can result in permanent impairment in memory and learning and may be a precursor to other neurological sequelae. Clinical treatments to ameliorate the effects of mTBI are lacking. Inhibition of microRNA-181a (miR-181a) is protective in several models of cerebral injury, but its role in mTBI has not been investigated. In the present study, miR-181a-5p antagomir was injected intracerebroventricularly 24 h prior to closed-skull cortical impact in young adult male mice. Paw withdrawal, open field, zero maze, Y maze, object location and novel object recognition tests were performed to assess neurocognitive dysfunction. Brains were assessed immunohistologically for the neuronal marker NeuN, the perineuronal net marker wisteria floribunda lectin (WFA), cFos, and the interneuron marker parvalbumin. Protein quantification was performed with immunoblots for synaptophysin and postsynaptic density 95 (PSD95). Fluorescent in situ hybridization was utilized to localize hippocampal miR-181a expression. MiR-181a antagomir treatment reduced neuronal miR-181a expression after mTBI, restored deficits in novel object recognition and increased hippocampal parvalbumin expression in the dentate gyrus. These changes were associated with decreased dentate gyrus hyperactivity indicated by a relative reduction in PSD95 and cFos expression. These results suggest that miR-181a inhibition may be a therapeutic approach to reduce hippocampal excitotoxicity and prevent cognitive dysfunction following mTBI.


Assuntos
Antagomirs/uso terapêutico , Lesões Encefálicas Traumáticas/terapia , Comportamento Exploratório/efeitos dos fármacos , Traumatismos Cranianos Fechados/terapia , MicroRNAs/antagonistas & inibidores , Parvalbuminas/biossíntese , Reconhecimento Psicológico/efeitos dos fármacos , Animais , Antagomirs/administração & dosagem , Antagomirs/farmacologia , Lesões Encefálicas Traumáticas/genética , Lesões Encefálicas Traumáticas/metabolismo , Córtex Cerebral/química , Córtex Cerebral/lesões , Córtex Cerebral/patologia , Simulação por Computador , Traumatismos Cranianos Fechados/genética , Traumatismos Cranianos Fechados/metabolismo , Hipocampo/química , Hipocampo/lesões , Hipocampo/patologia , Hiperalgesia/etiologia , Hiperalgesia/genética , Hiperalgesia/prevenção & controle , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/etiologia , Transtornos da Memória/genética , Transtornos da Memória/prevenção & controle , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/biossíntese , MicroRNAs/genética , Teste de Campo Aberto , Parvalbuminas/genética , Pré-Medicação , Distribuição Aleatória , Método Simples-Cego , Sinapses/química
5.
J Vis Exp ; (100): e52905, 2015 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-26168076

RESUMO

Traumatic brain injury (TBI) affects millions of people each year, causing impairment of physical, cognitive, and behavioral functions and death. Studies using Drosophila have contributed important breakthroughs in understanding neurological processes. Thus, with the goal of understanding the cellular and molecular basis of TBI pathologies in humans, we developed the High Impact Trauma (HIT) device to inflict closed head TBI in flies. Flies subjected to the HIT device display phenotypes consistent with human TBI such as temporary incapacitation and progressive neurodegeneration. The HIT device uses a spring-based mechanism to propel flies against the wall of a vial, causing mechanical damage to the fly brain. The device is inexpensive and easy to construct, its operation is simple and rapid, and it produces reproducible results. Consequently, the HIT device can be combined with existing experimental tools and techniques for flies to address fundamental questions about TBI that can lead to the development of diagnostics and treatments for TBI. In particular, the HIT device can be used to perform large-scale genetic screens to understand the genetic basis of TBI pathologies.


Assuntos
Modelos Animais de Doenças , Drosophila melanogaster/fisiologia , Traumatismos Cranianos Fechados/etiologia , Animais , Traumatismos Cranianos Fechados/genética , Traumatismos Cranianos Fechados/patologia
6.
J Cereb Blood Flow Metab ; 34(8): 1391-401, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24849666

RESUMO

A mild insult to the brain can sometimes trigger secondary brain injury, causing severe postconcussion syndrome, but the underlying mechanism is ill understood. We show here that secondary brain injury occurs consistently in mice lacking immediate early responsive gene X-1 (IEX-1), after a gentle impact to the head, which closely simulates mild traumatic brain injury in humans. The pathologic lesion was characterized by extensive cell death, widespread leukocyte infiltrates, and severe tissue loss. On the contrary, a similar insult did not induce any secondary injury in wild-type mice. Strikingly, noninvasive exposure of the injured head to a low-level laser at 4 hours after injury almost completely prevented the secondary brain injury in IEX-1 knockout mice. The low-level laser therapy (LLLT) suppressed proinflammatory cytokine expression like interleukin (IL)-1ß and IL-6 but upregulated TNF-α. Moreover, although lack of IEX-1 compromised ATP synthesis, LLLT elevated its production in injured brain. The protective effect of LLLT may be ascribed to enhanced ATP production and selective modulation of proinflammatory mediators. This new closed head injury model provides an excellent tool to investigate the pathogenesis of secondary brain injury as well as the mechanism underlying the beneficial effect of LLLT.


Assuntos
Lesões Encefálicas/prevenção & controle , Genes Precoces , Traumatismos Cranianos Fechados/radioterapia , Proteínas Imediatamente Precoces/deficiência , Terapia com Luz de Baixa Intensidade , Animais , Lesões Encefálicas/genética , Lesões Encefálicas/imunologia , Lesões Encefálicas/patologia , Citocinas/imunologia , Traumatismos Cranianos Fechados/genética , Traumatismos Cranianos Fechados/imunologia , Traumatismos Cranianos Fechados/patologia , Proteínas Imediatamente Precoces/genética , Escala de Gravidade do Ferimento , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Exame Neurológico , Prevenção Secundária
7.
Injury ; 43(8): 1264-70, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22341557

RESUMO

OBJECTIVE: Traumatic brain injury (TBI) is a major cause of death and disability in both children and the elderly. Mortality from TBI is said account for 1-2% of all deaths. One-third to one-half of all traumatic deaths is due to head injury. Of those who survive, the majority is left with significant disabilities, including 3% who remain in a vegetative state and only approximately 30% who make a good recovery. Microarray studies and other genomic techniques facilitate the discovery of new targets for the treatment of diseases, which aids in drug development, immunotherapeutics and gene therapy. Gene expression profiling or microarray analysis enables the measurement of thousands of genes in a single RNA sample. METHODS: In this study, adult Wistar-albino rats underwent TBI using a trauma device. Brain tissues and blood samples were taken for gene expression at 1, 12 and 48 h post-trauma and were then analysed via microarray. Total RNA was isolated using an RNeasy Mini Kit (QIAGEN-Sample & Assay Technologies, Hilden, Germany) and tested using a 2100 Bioanalyzer (Agilent Technologies, Palo Alto, CA). Overall changes in gene expression were evaluated using Agilent Whole Rat Genome 4 × 44 K oligonucleotide arrays and analysed with GeneSpring (GeneSpring 6.1, Silicon Genetics, Redwood City, CA) software. Only genes with a signal-to-noise ratio of above 2 in the experiments were included in the statistical analysis. RESULTS: ANOVA (p<0.05) was performed to identify differentially expressed probe sets. Additional filtering (minimum 2-fold change) was applied to extract the most differentially expressed genes based on the study groups (Control vs. 1st hour, Control vs. 12th hour, Control vs. 48th hour). Differentially expressed genes were detected via microarray analysis. A gene interaction-based network investigation of the genes that were identified via traditional microarray data analysis describes a significantly relevant gene network that includes the C1ql2, Cbnl, Sdc1, Bdnf, MMP9, and Cd47 genes, which were differentially expressed compared with the controls. CONCLUSIONS: In this study, we will review the current understanding of the genetic susceptibility of TBI with microarrays. Our results highlight the importance of genes that control the response of the brain to injury as well as the suitability of microarrays for identifying specific targets for further study.


Assuntos
Isquemia Encefálica/genética , Perfilação da Expressão Gênica , Traumatismos Cranianos Fechados/genética , Análise em Microsséries , Análise de Variância , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Expressão Gênica , Predisposição Genética para Doença , Traumatismos Cranianos Fechados/metabolismo , Traumatismos Cranianos Fechados/patologia , Masculino , Modelos Animais , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética
8.
J Neurotrauma ; 27(6): 1037-46, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20205514

RESUMO

We previously reported that tumor necrosis factor-alpha (TNF-alpha) and Fas receptor induce acute cellular injury, tissue damage, and motor and cognitive deficits after controlled cortical impact (CCI) in mice (Bermpohl et al. 2007 ); however, the TNF receptors (TNFR) involved are unknown. Using a CCI model and novel mutant mice deficient in TNFR1/Fas, TNFR2/Fas, or TNFR1/TNFR2/Fas, we tested the hypothesis that the combination of TNFR2/Fas is protective, whereas TNFR1/Fas is detrimental after CCI. Uninjured knockout (KO) mice showed no differences in baseline physiological variables or motor or cognitive function. Following CCI, mice deficient in TNFR2/Fas had worse post-injury motor and Morris water maze (MWM) performance than wild-type (WT) mice (p < 0.05 group effect for wire grip score and MWM performance by repeated measures ANOVA). No differences in motor or cognitive outcome were observed in TNFR1/Fas KO, or in TNFR2 or TNFR1 single KO mice, versus WT mice. Additionally, no differences in propidium iodide (PI)-positive cells (at 6 h) or lesion size (at 14 days) were observed between WT and TNFR1/Fas or TNFR2/Fas KO mice. Somewhat surprisingly, mice deficient in TNFR1/TNFR2/Fas also had PI-positive cells, lesion size, and motor and MWM deficits similar to those of WT mice. These data suggest a protective role for TNFR2/Fas in the pathogenesis of TBI. Further studies are needed to determine whether direct or indirect effects of TNFR1 deletion in TNFR2/Fas KO mice mediate improved functional outcome in TNFR1/TNFR2/Fas KO mice after CCI.


Assuntos
Lesões Encefálicas/genética , Traumatismos Cranianos Fechados/genética , Receptores do Fator de Necrose Tumoral/genética , Recuperação de Função Fisiológica/genética , Análise de Variância , Animais , Lesões Encefálicas/fisiopatologia , Contagem de Células , Genótipo , Traumatismos Cranianos Fechados/fisiopatologia , Camundongos , Camundongos Knockout , Atividade Motora/genética , Comportamento Espacial , Resultado do Tratamento
10.
Mol Med ; 15(7-8): 220-7, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19593405

RESUMO

Traumatic injuries frequently lead to infection, organ failure, and death. Health care providers rely on several injury scoring systems to quantify the extent of injury and to help predict clinical outcome. Physiological, anatomical, and clinical laboratory analytic scoring systems (Acute Physiology and Chronic Health Evaluation [APACHE], Injury Severity Score [ISS]) are utilized, with limited success, to predict outcome following injury. The recent development of techniques for measuring the expression level of all of a person's genes simultaneously may make it possible to develop an injury scoring system based on the degree of gene activation. We hypothesized that a peripheral blood leukocyte gene expression score could predict outcome, including multiple organ failure, following severe blunt trauma. To test such a scoring system, we measured gene expression of peripheral blood leukocytes from patients within 12 h of traumatic injury. cRNA derived from whole blood leukocytes obtained within 12 h of injury provided gene expression data for the entire genome that were used to create a composite gene expression score for each patient. Total blood leukocytes were chosen because they are active during inflammation, which is reflective of poor outcome. The gene expression score combines the activation levels of all the genes into a single number which compares the patient's gene expression to the average gene expression in uninjured volunteers. Expression profiles from healthy volunteers were averaged to create a reference gene expression profile which was used to compute a difference from reference (DFR) score for each patient. This score described the overall genomic response of patients within the first 12 h following severe blunt trauma. Regression models were used to compare the association of the DFR, APACHE, and ISS scores with outcome. We hypothesized that patients with a total gene response more different from uninjured volunteers would tend to have poorer outcome than those more similar. Our data show that for measures of poor outcome, such as infections, organ failures, and length of hospital stay, this is correct. DFR scores were associated significantly with adverse outcome, including multiple organ failure, duration of ventilation, length of hospital stay, and infection rate. The association remained significant after adjustment for injury severity as measured by APACHE or ISS. A single score representing changes in gene expression in peripheral blood leukocytes within hours of severe blunt injury is associated with adverse clinical outcomes that develop later in the hospital course. Assessment of genome-wide gene expression provides useful clinical information that is different from that provided by currently utilized anatomic or physiologic scores.


Assuntos
Sistemas de Apoio a Decisões Clínicas , Perfilação da Expressão Gênica/métodos , Traumatismos Cranianos Fechados/diagnóstico , Traumatismos Cranianos Fechados/genética , Índices de Gravidade do Trauma , Adolescente , Adulto , Feminino , Genômica/métodos , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico
11.
J Neurotrauma ; 26(9): 1521-33, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19257806

RESUMO

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. It causes progressive tissue atrophy and consequent neurological dysfunctions. TBI is accompanied by neuroinflammation, a process mediated largely by microglia. CD38 is an ectoenzyme that promotes transmembrane signaling via the synthesis of potent calcium mobilizing agents or via its receptor activity. CD38 is expressed in the brain in various cell types including microglia. In previous studies, we showed that CD38 regulates microglial activation and response to chemokines. In view of the important role of neuroinflammation in TBI and the effects of CD38 on microglial responses, the present study examines the role of CD38 in the recovery of mice from closed head injury (CHI), a model of focal TBI. For this purpose, CD38-deficient and wild-type (WT) mice were subjected to a similar severity of CHI and the effect of the injury on neurobehavioral and cognitive functions was assessed by the Neurological Severity Score (NSS) and the Object Recognition Test, at various time points post-injury. The results show that recovery after CHI (as indicated by the NSS) was significantly lower in CD38-deficient mice than in WT mice and that the object recognition performance after injury was significantly impaired in injured CD38-deficient mice than in WT mice. In addition, we also observed that the amount of activated microglia/macrophages at the injury site was significantly lower in CD38-deficient mice compared with WT mice. Taken together, our findings indicate that CD38 plays a beneficial role in the recovery of mice from CHI and that this effect is mediated, at least in part, via the effect of CD38 on microglia responses.


Assuntos
ADP-Ribosil Ciclase 1/fisiologia , Lesões Encefálicas/genética , Lesões Encefálicas/patologia , ADP-Ribosil Ciclase 1/genética , Animais , Astrócitos/patologia , Comportamento Animal , Lesões Encefálicas/psicologia , Traumatismos Cranianos Fechados/genética , Traumatismos Cranianos Fechados/patologia , Traumatismos Cranianos Fechados/psicologia , Processamento de Imagem Assistida por Computador , Imuno-Histoquímica , Macrófagos/patologia , Memória/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Microglia/patologia , Neurônios/patologia , Reconhecimento Psicológico/fisiologia , Recuperação de Função Fisiológica , Índices de Gravidade do Trauma
12.
J Neurotrauma ; 26(8): 1307-14, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19317611

RESUMO

Cerebral gene expression changes in response to traumatic brain injury will provide useful information in the search for future trauma treatment. In order to characterize the outcome of mild brain injury, we studied C57BL/6J mice in a weight-drop, closed head injury model. At various times post-injury, mRNA was isolated from neocortex and hippocampus and transcriptional alterations were studied using quantitative reverse transcriptase PCR and gene array analysis. At three days post-injury, the results showed unilateral injury responses, both in neocortex and hippocampus, with the main effect seen on the side of the skull hit by the dropping weight. Upregulated transcripts encoded products characterizing reactive astrocytes, phagocytes, microglia, and immune-reactive cells. Markers for oligodendrocytes and T-cells were not altered. Notably, strong differences in the responses among individual mice were seen (e.g., for the Gfap transcript expressed by reactive astrocytes and the chemokine Ccl3 transcript expressed by activated microglial cells). In conclusion, mild TBI chiefly activates transcripts leading to tissue signaling, inflammatory processes, and chemokine signaling, as in focal brain injury, suggesting putative targets for drug development.


Assuntos
Lesões Encefálicas/metabolismo , Traumatismos Cranianos Fechados/metabolismo , Hipocampo/metabolismo , Inflamação/metabolismo , Neocórtex/metabolismo , Análise de Variância , Animais , Astrócitos/metabolismo , Lesões Encefálicas/genética , Expressão Gênica , Traumatismos Cranianos Fechados/genética , Inflamação/genética , Masculino , Camundongos , Microglia/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fagócitos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não Paramétricas
13.
J Neural Transm (Vienna) ; 116(1): 1-12, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19018450

RESUMO

Microarray analysis was used to delineate gene expression patterns and profile changes following traumatic brain injury (TBI) in mice. A parallel microarray analysis was carried out in mice with TBI that were subsequently treated with minocycline, a drug proposed as a neuroprotectant in other neurological disorders. The aim of this comparison was to identify pathways that may be involved in secondary injury processes following TBI and potential specific pathways that could be targeted with second generation therapeutics for the treatment of neurotrauma patients. Gene expression profiles were measured with the compugen long oligo chip and real-time PCR was used to validate microarray findings. A pilot study of effect of minocycline on gene expression following TBI was also carried out. Gene ontology comparison analysis of sham TBI and minocycline treated brains revealed biological pathways with more genes differentially expressed than predicted by chance. Among 495 gene ontology categories, the significantly different gene ontology groups included chemokines, genes involved in cell surface receptor-linked signal transduction and pro-inflammatory cytokines. Expression levels of some key genes were validated by real-time quantitative PCR. This study confirms that multiple regulatory pathways are affected following brain injury and demonstrates for the first time that specific genes and molecular networks are affected by minocycline following brain injury.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Genoma , Traumatismos Cranianos Fechados/patologia , Minociclina/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Córtex Cerebral/metabolismo , Bases de Dados Genéticas , Modelos Animais de Doenças , Perfilação da Expressão Gênica/métodos , Traumatismos Cranianos Fechados/tratamento farmacológico , Traumatismos Cranianos Fechados/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Minociclina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Análise de Sequência com Séries de Oligonucleotídeos/métodos
14.
Ann Neurol ; 60(1): 65-72, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16718702

RESUMO

OBJECTIVE: Head injury is an inconsistently reported risk factor for Parkinson's disease (PD). Many related variables might confound this association, such as differences in childhood and adolescent lifestyles or genetically determined risk-taking behaviors. Twin studies circumvent some of these problems, because twins are genetically and environmentally much more similar than typical cases and control subjects. METHODS: We conducted a case-control study in 93 twin pairs discordant for PD ascertained from the National Academy of Sciences/National Research Council World War II Veteran Twins Cohort. RESULTS: A prior head injury with amnesia or loss of consciousness was associated with an increased risk for PD (odds ratio, 3.8; 95% confidence interval, 1.3-11; p = 0.014). Truncating observations 10 years before PD onset enhanced the association. Though less precise, the association was somewhat stronger in monozygotic than in dizygotic pairs. Risk increased further with a subsequent head injury (p trend = 0.022) and with head injuries requiring hospitalization. Duration of unconsciousness was not associated. In a subanalysis of 18 pairs concordant for PD, the twin with younger onset PD was more likely to have sustained a head injury, although numbers were small. INTERPRETATION: Our results suggest that mild-to-moderate closed head injury may increase PD risk decades later.


Assuntos
Traumatismos Cranianos Fechados/epidemiologia , Doença de Parkinson/epidemiologia , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Traumatismos Cranianos Fechados/genética , Humanos , Lactente , Modelos Logísticos , Prontuários Médicos , Rememoração Mental , Pessoa de Meia-Idade , Doença de Parkinson/genética , Fatores de Risco , Índice de Gravidade de Doença , Gêmeos Dizigóticos , Gêmeos Monozigóticos , Inconsciência/epidemiologia , Inconsciência/genética
15.
Neurosurgery ; 55(2): 416-24; discussion 424-5, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15271250

RESUMO

OBJECTIVE: Tumor necrosis factor alpha (TNFalpha) is elevated in some models of traumatic brain injury (TBI). However, it is unclear how TNFalpha messenger ribonucleic acid (mRNA) expression and protein levels are affected by injury severity and posttraumatic temperature modification. This study determined the regional and temporal profile of TNFalpha levels after moderate and severe TBI and assessed the effects of posttraumatic hypothermia or hyperthermia on this proinflammatory cytokine. METHODS: Adult male Sprague-Dawley rats were subjected to sham procedures (no injury), moderate fluid-percussion TBI (1.8-2.2 atm), or severe fluid-percussion TBI (2.4-2.6 atm). After 1 to 72 hours of survival, animals were killed, and brain samples, cerebrospinal fluid, and serum were harvested for enzyme-linked immunosorbent assay quantification of TNFalpha levels. In a subsequent study, a 3-hour period of posttraumatic hypothermia (33 degrees C) or hyperthermia (39.5 degrees C) was applied, followed by immediate killing and cytokine assay. Another group was subjected to moderate TBI (1.8-2.2 atm), followed by killing at 15 minutes or at 1, 3, or 24 hours for TNFalpha reverse transcriptase-polymerase chain reaction analysis. RESULTS: A significant increase in TNFalpha mRNA and protein levels in cellular lysates of injured cortex and ipsilateral hippocampus was noted by 1 hour after TBI; it was sustained to 3 hours, followed by a rapid decline. Increased injury severity was associated with increased protein levels at remote injury sites and in the injured cerebral cortex at 72 hours. Posttraumatic hypothermia significantly reduced TNFalpha mRNA expression in the hippocampus compared with that in normothermic rats. In contrast, no temperature effects on TNFalpha protein levels were documented. CONCLUSION: Rapid and marked increase in TNFalpha mRNA expression and protein levels follows moderate and severe TBI. Injury severity and posttraumatic temperature play a modest but significant role on TNFalpha expression and protein levels. These findings suggest that the effects of posttraumatic temperature on histopathological and behavioral outcome primarily may involve secondary mediators that do not operate directly through their effect on TNFalpha.


Assuntos
Traumatismos Cranianos Fechados/genética , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/genética , Fator de Necrose Tumoral alfa/genética , Animais , Edema Encefálico/genética , Edema Encefálico/patologia , Córtex Cerebral/lesões , Córtex Cerebral/patologia , Líquido Cefalorraquidiano/fisiologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Regulação da Expressão Gênica/fisiologia , Traumatismos Cranianos Fechados/patologia , Hipocampo/lesões , Hipocampo/patologia , Hipertermia Induzida , Hipotermia Induzida , Escala de Gravidade do Ferimento , Masculino , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa
16.
J Neurosurg ; 98(2): 302-6, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12593615

RESUMO

OBJECT: The presence of the apolipoprotein E-epsilon4 (APOE-epsilon4) allele is reported to be associated with poor outcome after traumatic brain injury (TBI). This study was performed to determine if the presence of the APOE-epsilon4 allele influenced outcome in a cohort of black patients with TBI who had homogeneous neuropathological findings. METHODS: Venous blood was collected at the time of admission to determine the APOE genotype in black Zulu-speaking patients who presented with traumatic cerebral contusions. The frequency of the APOE-epsilon4 allele's appearance was correlated with outcome at a minimum of 6 months of follow up. Univariate and multivariate analyses were performed to determine independent risk factors and to control for confounding factors. In 110 black Zulu-speaking patients with traumatic cerebral contusions, genotypes for APOE were analyzed. Eleven of 45 (24.4%) with the APOE-epsilon4 allele experienced a poor outcome, compared with 10 (15.4%) of 65 without this allele (p = 0.34). Both patients with homozygous APOE-epsilon4 alleles experienced a good outcome (Glasgow Outcome Score 5). Univariate and multivariate analysis revealed no significant relationship in patients with the APOE-epsilon4 allele with regard to age, admission Glasgow Comas Scale score, contusion volume, type of neurosurgical management, and outcome. The risk of a poor outcome was, however, greater in patients with the APOE-epsilon4 allele (relative risk 1.59; 95% confidence interval 0.74-3.42). CONCLUSIONS: The authors recorded no relationship between APOE-epsilon4 allele status and outcome after TBI in black patients. Given the high regional susceptibility to the APOE gene, further studies, possibly even community-based investigations and studies conducted in other geographic areas, are probably warranted.


Assuntos
Apolipoproteínas E/genética , População Negra/genética , Negro ou Afro-Americano , Lesões Encefálicas/etnologia , Lesões Encefálicas/genética , Traumatismos Cranianos Fechados/etnologia , Traumatismos Cranianos Fechados/genética , Avaliação de Resultados em Cuidados de Saúde , Polimorfismo Genético/genética , Adolescente , Adulto , Apolipoproteína E4 , Lesões Encefálicas/terapia , Criança , Estudos de Coortes , Feminino , Seguimentos , Genótipo , Traumatismos Cranianos Fechados/terapia , Humanos , Masculino , Pessoa de Meia-Idade , África do Sul/etnologia
17.
Neuroscience ; 101(4): 879-84, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-11113336

RESUMO

Apolipoprotein E, the major brain lipid-binding protein, is expressed in humans as three common isoforms (E2, E3 and E4). Previous studies revealed that the allele apolipoprotein E4 is a major genetic risk factor of Alzheimer's disease and that traumatic brain injury is associated with increased risk for developing this disease. Furthermore, it has been suggested that the effects of traumatic head injury and apolipoprotein E4 in Alzheimer's disease are synergistic. To test the hypothesis that the apolipoprotein E genotype affects susceptibility to brain injury, we subjected transgenic mice, expressing either human apolipoprotein E3 or human apolipoprotein E4 on a null mouse apolipoprotein E background and apolipoprotein E-deficient knockouts, to closed head injury and compared mortality, neurological recovery and the extent of brain damage of the survivors. More than 50% of the transgenic mice expressing human apolipoprotein E4 died following closed head injury, whereas only half as many of the transgenic mice expressing human apolipoprotein E3, and of the control and apolipoprotein E-deficient mice died during this period (P<0.02). A neurological severity score used for clinical assessment of the surviving mice up to 11 days after closed head injury revealed that the four mouse groups displayed similar severity of damage at 1h following injury. At three and 11 days post-injury, however, the neurological severity scores of the transgenic mice expressing human apolipoprotein E3 were significantly lower than those of the other three groups whose scores were similar, indicating better recovery of the transgenic mice expressing human apolipoprotein E3. Histopathological examination of the mice performed 11 days post-injury revealed, consistent with the above neurological results, that the size of the damaged brain area of the transgenic mice expressing human apolipoprotein E3 was smaller than that of the other head-injured groups. These findings show that transgenic mice expressing human apolipoprotein E4 are more susceptible than those expressing apolipoprotein E3 to closed head injury. We suggest that this effect is due to both a protective effect of apolipoprotein E3 and an apolipoprotein E4-related pathological function.


Assuntos
Apolipoproteínas E/genética , Predisposição Genética para Doença , Traumatismos Cranianos Fechados/genética , Alelos , Animais , Apolipoproteína E4 , Encéfalo/patologia , Traumatismos Cranianos Fechados/mortalidade , Traumatismos Cranianos Fechados/patologia , Traumatismos Cranianos Fechados/fisiopatologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos/genética , Sistema Nervoso/fisiopatologia , Fármacos Neuroprotetores/metabolismo , Valores de Referência
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