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Preconditioning Triggered by Carbon Monoxide (CO) Provides Neuronal Protection Following Perinatal Hypoxia-Ischemia.
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Resumo(s)
Perinatal hypoxia-ischemia is a major cause of acute mortality in newborns and cognitive and motor impairments in children. Cerebral hypoxia-ischemia leads to excitotoxicity and necrotic and apoptotic cell death, in which mitochondria play a major role. Increased resistance against major damage can be achieved by preconditioning triggered by subtle insults. CO, a toxic molecule that is also generated endogenously, may have a role in preconditioning as low doses can protect against inflammation and apoptosis. In this study, the role of CO-induced preconditioning on neurons was addressed in vitro and in vivo. The effect of 1 h of CO treatment on neuronal death (plasmatic membrane permeabilization and chromatin condensation) and bcl-2 expression was studied in cerebellar granule cells undergoing to glutamate-induced apoptosis. CO's role was studied in vivo in the Rice-Vannucci model of neonatal hypoxia-ischemia (common carotid artery ligature +75 min at 8% oxygen). Apoptotic cells, assessed by Nissl staining were counted with a stereological approach and cleaved caspase 3-positive profiles in the hippocampus were assessed. Apoptotic hallmarks were analyzed in hippocampal extracts by Western Blot. CO inhibited excitotoxicity-induced cell death and increased Bcl-2 mRNA in primary cultures of neurons. In vivo, CO prevented hypoxia-ischemia induced apoptosis in the hippocampus, limited cytochrome c released from mitochondria and reduced activation of caspase-3. Still, Bcl-2 protein levels were higher in hippocampus of CO pre-treated rat pups. Our results show that CO preconditioning elicits a molecular cascade that limits neuronal apoptosis. This could represent an innovative therapeutic strategy for high-risk cerebral hypoxia-ischemia patients, in particular neonates.
Descrição
This work was supported by the Portuguese Fundacao para a Ciencia e Tecnologia (PTDC/SAU-NEU/64327/2006; PTDCS/SAU-NEU/098747/2008) and the Portuguese Fundacao para a Ciencia e Tecnologia, for HLAV's SFRH/BPD/27125/2006 and for CSFQ's SFRH/BD/43387/2008 fellowships. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Palavras-chave
RAT MODEL INJURY MITOCHONDRIAL-MEMBRANE PERMEABILIZATION CEREBRAL-ISCHEMIA NEUROPROTECTION TOLERANCE CELL-DEATH REDUCES APOPTOSIS BRAIN-DAMAGE HEME OXYGENASE-1