Bcl-w Expression and Localization in Brain Ischemia
Bcl-w is a newly described cell death-suppressor member of the Bcl-2 gene family. As these genes may have a role in the outcome of ischemic brain injury, the regional expression of Bcl-w protein in rat brain was examined at 6-72 h after 90 min transient middle cerebral artery occlusion. Bcl-w protein, while constitutively expressed at low levels in non-ischemic brain, was found to be overexpressed in ischemic brain at all time points studied. Up regulation of Bcl-w protein was particularly abundant in the penumbral region of the cortex and mainly in cells lacking DNA-fragmentation. In the cortical penumbra, Bcl-w protein was predominantly detected in neurons and showed mitochondrial localization, as determined by double-label immunohistochemistry. Bcl-w expression was also detectable, to a lesser extent, in reactive astrocytes in the infarct border zone and in micro vessel walls in the infarct regions. At the mechanistic level, incubation of isolated brain mitochondria with the addition of recombinant BAX or high concentrations of calcium resulted in release of cytochrome c from the mitochondria. In the presence of recombinant Bcl-w protein, however, the release of cytochrome c induced by BAX or calcium was largely inhibited. Further, recombinant Bcl-w protein inhibited calcium-induced loss of mitochondrial trans membrane potential, indicative of permeability transition, in a dose-dependent manner. These results suggest that Bcl-w is an endogenous neuroprotectant against ischemic neuronal death and that like its analogues such as Bcl-2 and Bcl-xL, Bcl-w may achieve this protection via the mitochondrial death-regulatory pathway.
KeywordsPermeability Ischemia Chrome Attenuation Isoflurane
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