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1.
Resuscitation ; 78(1): 85-91, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18455860

RESUMO

BACKGROUND: Global cerebral ischaemia after cardiac arrest (CA) leads to programmed cell death (PCD) with characteristic signs of apoptosis in selectively vulnerable areas of the brain. The activation of caspase-3, an executioner caspase, plays a key role in the apoptotic cascade. We, therefore, studied the effects of the application of the specific caspase-3 inhibitor zDEVD-FMK on neurological outcome and neuronal cell death after experimental CA in rats. METHODS: A 6-min CA was induced in anaesthetised and mechanically ventilated male Wistar rats. After cardiopulmonary resuscitation (CPR) and restoration of spontaneous circulation (ROSC) the animals were randomised to two groups to receive a continuous intracerebroventricular (i.c.v.) infusion for 7 days of zDEVD-FMK or placebo (artificial cerebrospinal fluid, CSF). At 24h, 3 and 7 days after ROSC, animals were tested according to a neurological deficit score (NDS). Seven days after ROSC, coronal sections of the brain were taken at the dorsal hippocampal level and analysed with cresyl-violet staining, the TUNEL technique and a caspase activity assay. Viable and TUNEL-positive neurons were counted in the hippocampal CA-1 sector. RESULTS: The NDS demonstrated severe deficits 1 and 3 days after ROSC, which resolved by 7 days with no difference between the two groups. At 7 days after ROSC neuronal death could be detected using cresyl-violet and TUNEL staining with no difference between the groups. CONCLUSION: We conclude that zDEVD-FMK administration has no effect on neurological outcome and PCD after global cerebral ischaemia following CA in rats. Other mechanisms or pathways must be identified in the pathophysiology of PCD after CA.


Assuntos
Clorometilcetonas de Aminoácidos/farmacologia , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/etiologia , Inibidores de Caspase , Parada Cardíaca/complicações , Clorometilcetonas de Aminoácidos/administração & dosagem , Animais , Morte Celular/efeitos dos fármacos , Marcação In Situ das Extremidades Cortadas , Masculino , Distribuição Aleatória , Ratos , Ratos Wistar , Estatísticas não Paramétricas
2.
Anesthesiology ; 99(1): 112-21, 2003 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12826850

RESUMO

BACKGROUND: Global cerebral ischemia is associated with delayed neuronal death. Given the role of caspases in apoptosis, caspase inhibitors may provide neuronal protection after cardiac arrest. To this end, the authors generated a transgenic rat line expressing baculovirus p35, a broad-spectrum caspase inhibitor, in central neurons. Its effects were evaluated on neuronal cell death and outcome after global cerebral ischemia. METHODS: Global cerebral ischemia was induced by cardiocirculatory arrest. After 6 min, animals were resuscitated by controlled ventilation, extrathoracic cardiac massage, epinephrine, and electrical countershocks. Neuronal death was assessed after 7 days by histologic evaluation of the hippocampal cornu ammonis 1 sector. Postischemic outcome was assessed by determination of overall survival and according to neurologic deficit scores 24 h, 3 days, and 7 days after resuscitation. RESULTS: The rate of 7-day survival after cardiac arrest for the transgenic rats (85%) was significantly higher than that for the nontransgenic controls (52%; P < 0.05). However, no differences were observed either in the number of terminal deoxynucleotidyltransferase-mediated d-uracil triphosphate-biotin nick end-labeling-positive cells or viable neurons in the cornu ammonis 1 sector or in the neurologic deficit score when comparing surviving transgenic and nontransgenic rats. These findings suggest that neuronal apoptosis after cardiac arrest is not primarily initiated by activation of caspases. CONCLUSION: Expression of baculovirus p35 can improve survival after cardiac arrest in rats, but the mode and site of action remain to be elucidated.


Assuntos
Baculoviridae/metabolismo , Reanimação Cardiopulmonar , Inibidores de Caspase , Inibidores Enzimáticos/metabolismo , Parada Cardíaca/fisiopatologia , Proteínas Virais/fisiologia , Animais , Animais Geneticamente Modificados , Northern Blotting , Southern Blotting , Western Blotting , Química Encefálica/genética , Isquemia Encefálica/patologia , Morte Celular/fisiologia , Eletrochoque , Hipocampo/patologia , Hibridização In Situ , Marcação In Situ das Extremidades Cortadas , Proteínas Inibidoras de Apoptose , Microinjeções , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/patologia , Neurônios/patologia , Ratos , Ratos Wistar , Sobrevida , Proteínas Virais/biossíntese , Proteínas Virais/genética
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