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Caspase‐dependent and caspase‐independent signalling of apoptosis in the penumbra following middle cerebral artery occlusion in the adult rat
Author(s) -
Ferrer I.,
Friguls B.,
Dalfó E.,
Justicia C.,
Planas A. M.
Publication year - 2003
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1046/j.1365-2990.2003.00485.x
Subject(s) - penumbra , apoptosis , programmed cell death , cytochrome c , middle cerebral artery , ischemia , caspase , biology , caspase 3 , microbiology and biotechnology , cytosol , pathology , medicine , biochemistry , enzyme
Transient focal ischaemia by middle cerebral artery occlusion (MCAO) may produce cell death, but the mechanisms leading to cell death differ in the infarct core and in the penumbra, the immediate zone surrounding the infarct core. In the present study, transient focal ischaemia to adult rats was produced by intraluminal occlusion of the middle cerebral artery for 1 h followed by 0 h ( n = 6), 1 h ( n = 10), 4 h ( n = 8), 6 h ( n = 2) and 12 h ( n = 3) of reperfusion. The present model of ischaemia causes a large cortico‐striatal infarct extending through the mediolateral cortex and dorsolateral striatum at 12 h. The expression and subcellular distribution of several proteins involved in apoptosis have been examined in the penumbra and in the infarct core by using combined methods of immunohistochemistry, cell subfractionation and Western blotting. Transient focal ischaemia by MCAO results in activation of complex signal pathways for cell death in the penumbra. Increased expression of Bcl‐2 and Bax, but not of Bcl‐x, occurs in the penumbra at the time when Bax translocates from the cytosol to the mitochondria, cytochrome c is released to the cytoplasm and active caspase‐3 is expressed. Bax translocation, cytochrome c release and active caspase‐3 are observed at 4 h, but not at 1 h, following reperfusion, and together indicate activation of the caspase‐dependent pathway of apoptosis in the penumbra. In contrast, reduced Bax expression but not Bax translocation and cytochrome c release occurs in the infarct core, thus suggesting apoptosis signals restricted to the penumbra. In addition, increased expression of an apoptosis‐inducing factor in the cytoplasm and nuclei of selected cells shows, for the first time, activation of the caspase‐independent mitochondrial pathway in the penumbra following transient focal ischaemia and reperfusion.