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dc.contributor.authorZhu, Changlian 1964-en
dc.description.abstractAims: To investigate the mechanisms of neuronal cell death after hypoxia-ischemia in the developing brain.Methods: Rats or mice were subjected to left common carotid artery ligation plus hypoxia. Animals were sacrificed at certain time points after hypoxia-ischemia. The brains were collected for immunohistochemistry, western blotting, enzyme activity measurement and brain injury assessment.Results: Caspase-3 was activated after HI, and reached a peak level at 24 h post-HI. Immunoreactivity for active caspase-3 corresponded well with hybridization with an oligonucleotide hairpin probe, a marker of double-stranded DNA breaks with one nucleotide overhang in the 3 end. Calpain activation and, subsequently, Caspase-3 activation occurred after HI. Calpain inhibitors reduced cleavage of pro-caspase-3 into a 29 kDa product and decreased the activation of caspase-3. Calpain activation facilitated further activation of caspase-3. After HI, AIF was lost from mitochondria and the levels increased in nuclei (translocation) and, subsequently, signs of caspase-independent DNA damage occurred. AIF release occurred earlier than that of cytochrome c and correlated with tissue damage. A broad spectrum caspase inhibitor markedly reduced activation of caspase activity after HI, but still did not confer tissue protection. Nitrotyrosine formation preceded AIF release and caspase-3 activation. Nitrotyrosine is an early marker of cellular injury. Combined inhibition of nNOS and iNOS by 2-iminobiotin(a known neuroprotectant)reduced nitrotyrosine formation and caspase-3 activation. Immaturity greatly influences the outcome of HI, but not in a linear fashion. Apoptosis-related mechanisms of neuronal cell death after HI are much more prevalent in the developing brain, including both caspase-dependent and caspase-independent pathways.Conclusions: Several apoptotic mechanisms are activated in neonatal brain after HI. Inhibition of apoptotic mechanisms may be a fruitful neuroprotective strategy. Brain injury and neuronal cell death after hypoxia-ischemia is age-related and prevention and treatment of brain injury need to be adjusted to the developmental level.en
dc.subjecthypoxia ischemiaen
dc.subjectcell deathen
dc.subjectapoptosis-inducing factoren
dc.subjectnitric oxideen
dc.titleCaspase-dependent and caspase-independent neuronal injury in the developing brainen
dc.type.svepDoctoral thesisen
dc.gup.originGöteborgs universitet/University of Gothenburgeng
dc.gup.departmentDepartment of Physiologyeng
dc.gup.departmentAvdelningen för fysiologiswe
dc.gup.defenceplaceÅke Göransson, F2421, Institutionen för fysiologi och farmakologi, Avdelningen för medicinsk fysik, Medicinaregatan 11, kl. 09.00en

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