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Early and Sequential Recruitment of Apoptotic Effectors after Focal Permanent Ischemia in Mice

Abstract : In experimental models of cerebral ischemia, cells within the damaged territory die by necrosis and by apoptosis that contributes to the expansion of the insult. Apoptotic machinery mobilizes intracellular processes such as induction of Bcl-2 family members, activation of the proteolytic cascade including the caspases, and cleavage of caspase substrates, such as poly(ADP–ribose) polymerase or PARP. Mitochondria play a pivotal role in controlling apoptosis by releasing cytochrome c and modulating redox state, both under the regulation of manganese superoxide dismutase (Mn SOD) via superoxide anion detoxification. The implication and the kinetics of such events in apoptosis induced after focal permanent ischemia in mice remains to be studied. In a paradigm of ischemic insult induced by occlusion of the middle cerebral artery (MCAO) in mice, we showed by immunohistochemistry a constitutive expression of caspase-3 that is enhanced after MCAO in neurons localized within the infarcted zone. As a function of time intervals after MCAO, the cytochrome c amount increased in the cytosolic fraction of ischemic cortical extracts. The kinetics of the release was in concordance with the expression of caspase-3 and the subsequent cleavage of PARP appearing before the internucleosomal fragmentation of DNA, the ultimate step of apoptosis. When the apoptotic markers progressively appeared, no changes of Mn SOD activity or Mn SOD expression were detected after MCAO. We can therefore speculate that the recruitment of Mn SOD did not participate per se in the release of cytochrome c elicited after permanent focal ischemia.
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https://hal-normandie-univ.archives-ouvertes.fr/hal-01762040
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Submitted on : Monday, April 9, 2018 - 3:52:14 PM
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Guégan C, Brigitte Sola. Early and Sequential Recruitment of Apoptotic Effectors after Focal Permanent Ischemia in Mice. Brain Research, Elsevier, 2000, 856 (1-2), pp.93-100. ⟨10.1016/s0006-8993(99)02347-1⟩. ⟨hal-01762040⟩

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