Dynamics of regional brain metabolism and gene expression after middle cerebral artery occlusion in mice

The evolution of brain infarcts during permanent occlusion of the middle ce rebral artery (MCA) was studied in mice using multiparametric imaging techn iques. Regional protein synthesis and the regional tissue content of ATP we re measured on adjacent cryostat sections at increasing intervals after vas cular occlusion ranging from 1 hour to 3 days. The observed changes were co rrelated with the expression of the mRNA of hsp70, c-fos, c-jun, and junB, as well as the distribution of DNA double-strand breaks visualized by termi nal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (T UNEL). One hour after MCA occlusion, the tissue volume with suppressed prot ein synthesis was distinctly larger than that in which ATP was depleted. Wi th ongoing ischemia time, the ATP-depleted area gradually expanded and, wit hin 1 day, merged with the region of suppressed protein synthesis. Expressi on of hsp70 mRNA occurred mainly in the penumbra (defined as the region of suppressed protein synthesis but preserved ATP). peaking at 3 hours after v ascular occlusion. Expression of the immediate-early genes c-jun, c-fos, an d junB increased both in the penumbra and the periinfarct normal tissue alr eady at 1 hour after vascular occlusion, with slightly different regional a nd temporal patterns for each of these genes. DNA fragmentations were clear ly confined to neurons: they appeared after 1 clay in the infarct core (de fined as the region of suppressed ATP) and never were detected in the penum bra. The late appearance of TUNEL after infarcts had reached their final si ze and the absence in the penumbra points against a major pathogenetic role of apoptosis. Permanent MCA occlusion in mice thus produces a gradually ex panding infarct, the final size of which is heralded by the early inhibitio n of protein synthesis.