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1.
J Neurosurg ; 116(6): 1368-78, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22462511

RESUMO

OBJECT: This study investigates the outcome after traumatic brain injury (TBI) in mice lacking the essential DNA repair gene xeroderma pigmentosum group A (XPA). As damage to DNA has been implicated in neuronal cell death in various models, the authors sought to elucidate whether the absence of an essential DNA repair factor would affect the outcome of TBI in an experimental setting. METHODS: Thirty-seven adult mice of either wild-type (n = 18) or XPA-deficient ("knock-out" [n = 19]) genotype were subjected to controlled cortical impact experimental brain trauma, which produced a focal brain injury. Sham-injured mice of both genotypes were used as controls (9 in each group). The mice were subjected to neurobehavoral tests evaluating learning/acquisition (Morris water maze) and motor dysfunction (Rotarod and composite neuroscore test), pre- and postinjury up to 4 weeks. The mice were killed after 1 or 4 weeks, and cortical lesion volume, as well as hippocampal and thalamic cell loss, was evaluated. Hippocampal staining with doublecortin antibody was used to evaluate neurogenesis after the insult. RESULTS: Brain-injured XPA(-/-) mice exhibited delayed recovery from impairment in neurological motor function, as well as pronounced cognitive dysfunction in a spatial learning task (Morris water maze), compared with injured XPA(+/+) mice (p < 0.05). No differences in cortical lesion volume, hippocampal damage, or thalamic cell loss were detected between XPA(+/+) and XPA(-/-) mice after brain injury. Also, no difference in the number of cells stained with doublecortin in the hippocampus was detected. CONCLUSIONS: The authors' results suggest that lack of the DNA repair factor XPA may delay neurobehavioral recovery after TBI, although they do not support the notion that this DNA repair deficiency results in increased cell or tissue death in the posttraumatic brain.


Assuntos
Lesões Encefálicas/genética , Lesões Encefálicas/fisiopatologia , Córtex Cerebral/lesões , Córtex Cerebral/fisiopatologia , Reparo do DNA/genética , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Destreza Motora/fisiologia , Regeneração Nervosa/genética , Equilíbrio Postural/fisiologia , Reflexo de Endireitamento/fisiologia , Proteína de Xeroderma Pigmentoso Grupo A/genética , Animais , Lesões Encefálicas/patologia , Morte Celular/genética , Morte Celular/fisiologia , Córtex Cerebral/patologia , Genótipo , Hipocampo/patologia , Hipocampo/fisiopatologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Tálamo/patologia , Tálamo/fisiopatologia
2.
J Cereb Blood Flow Metab ; 28(6): 1186-95, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18301432

RESUMO

Uncoupling protein 2 (UCP2) is upregulated in the brain after sublethal ischemia, and overexpression of UCP2 is neuroprotective in several models of neurodegenerative disease. We investigated if increased levels of UCP2 diminished neuronal damage after global brain ischemia by subjecting mice overexpressing UCP2 (UCP2/3tg) and wild-type littermates (wt) to a 12-min global ischemia. The histopathological outcome in the cortex, hippocampus, striatum, and thalamus was evaluated at 4 days of recovery, allowing maturation of the selective neuronal death. Global ischemia led to extensive cell death in the striatum, thalamus, and in the CA1 and CA2, and less-pronounced cell death in the CA3 and dentate gyrus (DG) hippocampal subfields. Histologic damage was significantly lower in the ventral posterolateral VPL and medial VPM thalamic nuclei in UCP2/3tg animals compared with wt. These thalamic regions showed a larger increase in UCP2 expression in UCP2/3tg compared with wt animals relative to the nonprotected DG. In the other regions studied, the histologic damage was lower or equal in UCP2/3tg animals compared with wt. Consequently, neuroprotection in the thalamus correlated with a high expression of UCP2, which is neuroprotective in a number of models of neurodegenerative diseases.


Assuntos
Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Canais Iônicos/metabolismo , Proteínas Mitocondriais/metabolismo , Neurônios/metabolismo , Tálamo/citologia , Regulação para Cima , Animais , Isquemia Encefálica/genética , Morte Celular , Humanos , Canais Iônicos/genética , Camundongos , Camundongos Transgênicos , Proteínas Mitocondriais/genética , Neurônios/citologia , Neurônios/patologia , Tálamo/patologia , Proteína Desacopladora 2 , Proteína Desacopladora 3
3.
Cerebrovasc Dis ; 25(3): 268-78, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18292653

RESUMO

Stroke poses a massive burden of disease, yet we have few effective therapies. The paucity of therapeutic options stands contrary to intensive research efforts. The failure of these past investments demands a thorough re-examination of the pathophysiology of ischaemic brain injury. Several critical areas hold the key to overcoming the translational roadblock: (1) vascular occlusion: current recanalization strategies have limited effectiveness and may have serious side effects; (2) complexity of stroke pathobiology: therapy must acknowledge the 'Janus-faced' nature of many stroke targets and must identify endogenous neuroprotective and repair mechanisms; (3) inflammation and brain-immune-system interaction: inflammation contributes to lesion expansion, but is also instrumental in lesion containment and repair; stroke outcome is modulated by the interaction of the injured brain with the immune system; (4) regeneration: the potential of the brain for reorganization, plasticity and repair after injury is much greater than previously thought; (5) confounding factors, long-term outcome and predictive modelling. These 5 areas are linked on all levels and therefore need to be tackled by an integrative approach and innovative therapeutic strategies.


Assuntos
Anti-Inflamatórios/uso terapêutico , Pesquisa Biomédica , Isquemia Encefálica/complicações , Encéfalo/efeitos dos fármacos , Precondicionamento Isquêmico , Fármacos Neuroprotetores/uso terapêutico , Acidente Vascular Cerebral/terapia , Terapia Trombolítica , Animais , Anti-Inflamatórios/farmacologia , Encéfalo/irrigação sanguínea , Encéfalo/patologia , Encéfalo/fisiopatologia , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/terapia , Circulação Cerebrovascular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/fisiopatologia , Inflamação/tratamento farmacológico , Regeneração Nervosa/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Projetos de Pesquisa , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/fisiopatologia , Terapia Trombolítica/efeitos adversos , Resultado do Tratamento
4.
J Neurochem ; 96(1): 14-29, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16300643

RESUMO

In order to identify biological processes relevant for cell death and survival in the brain following stroke, the postischemic brain transcriptome was studied by a large-scale cDNA array analysis of three peri-infarct brain regions at eight time points during the first 24 h of reperfusion following middle cerebral artery occlusion in the rat. K-means cluster analysis revealed two distinct biphasic gene expression patterns that contained 44 genes (including 18 immediate early genes), involved in cell signaling and plasticity (i.e. MAP2K7, Sprouty2, Irs-2, Homer1, GPRC5B, Grasp). The first gene induction phase occurred at 0-3 h of reperfusion, and the second at 9-15 h, and was validated by in situ hybridization. Four gene clusters displayed a progressive increase in expression over time and included 50 genes linked to cell motility, lipid synthesis and trafficking (i.e. ApoD, NPC1, G3P-dehydrogenase1, and Choline kinase) or cell death-regulating genes such as mitochondrial CLIC. We conclude that a biphasic transcriptional up-regulation of the brain-derived neurotrophic factor (BDNF)-G-protein coupled receptor (GPCR)-mitogen-activated protein (MAP) kinase signaling pathways occurs in surviving tissue, concomitant with a progressive and persistent activation of cell proliferation signifying tissue regeneration, which provide the means for cell survival and postischemic brain plasticity.


Assuntos
Química Encefálica/genética , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , Encéfalo/patologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/fisiologia , Acidente Vascular Cerebral/metabolismo , Animais , Autorradiografia , Isquemia Encefálica/patologia , Proliferação de Células , Sobrevivência Celular/fisiologia , DNA Complementar/biossíntese , DNA Complementar/genética , Hibridização In Situ , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/patologia , Masculino , Família Multigênica/genética , Regeneração Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Análise de Sequência com Séries de Oligonucleotídeos , RNA/biossíntese , RNA/isolamento & purificação , Ratos , Ratos Wistar , Sinapses/fisiologia , Ativação Transcricional
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