ALTERED EXPRESSION OF BCL-2, BCL-X, BAX, AND C-FOS COLOCALIZES WITH DNA FRAGMENTATION AND ISCHEMIC CELL-DAMAGE FOLLOWING MIDDLE CEREBRAL-ARTERY OCCLUSION IN RATS

Permanent occlusion of the middle cerebral artery in rats was used to assess the effects of focal ischemia on the expression of members of t he bcl-2 family which have been implicated in the regulation of progra med cell death. intraluminal occlusion of one middle cerebral artery f or 6 h resulted in histologically detectable brain damage within the i psilateral caudate putamen, basolateral cortex and parts of the thalam us. Zn the infarcted basolateral cortex and thalamus fragmentation of DNA was detected in many nuclei using in-situ end-labeling of DNA brea ks by terminal transferase, whereas only scattered labeled nuclei were visible in the infarcted caudate putamen. Immunohistochemical analysi s revealed activation of c-Fos in the infarcted cortex and thalamus an d in the non-infarcted cingulate cortex as has been shown by others. A decrease in immunoreactivity for Bcl-2, and Bcl-X and an increase in immunostaining for Bar was observed exclusively in neurons within the ischemic cortex and thalamus, Within the infarcted caudate putamen, ho wever, protein levels of all bcl-2 family members declined and c-Fos r emained absent, By reverse transcription and polymerase chain reaction it was demonstrated that levels of bcl-2 mRNA markedly decreased in t he ipsilateral hemisphere, whereas the amount of bax mRNA was elevated . These findings suggest that a shift in the ratio of cell death repre ssor Bcl-2 to cell death effector Bar and a concomitant activation of c-Fos may contribute to neuronal apoptosis in the infarcted thalamus a nd cortex.