Aged rats recover poorly after unilateral stroke, whereas young rats recover readily possibly with the help from the contralateral, healthy hemisphere. In this study we asked whether anomalous, age-related changes in the transcriptional activity in the brains of aged rats could be one underlying factor contributing to reduced functional recovery. We analysed gene expression in the periinfarct and contralateral areas of 3-month- and 18-month-old Sprague Dawley rats. Our experimental end-points were cDNA arrays containing genes related to hypoxia signalling, DNA damage and apoptosis, cellular response to injury, axonal damage and re-growth, cell lineage differentiation, dendritogenesis and neurogenesis. The major transcriptional events observed were: (i) Early up-regulation of DNA damage and down-regulation of anti-apoptosis-related genes in the periinfarct region of aged rats after stroke; (ii) Impaired neurogenesis in the periinfarct area, especially in aged rats; (iii) Impaired neurogenesis in the contralateral (unlesioned) hemisphere of both young and aged rats at all times after stroke and (iv) Marked up-regulation, in aged rats, of genes associated with inflammation and scar formation. These results were confirmed with quantitative real-time PCR. We conclude that reduced transcriptional activity in the healthy, contralateral hemisphere of aged rats in conjunction with an early up-regulation of DNA damage-related genes and pro-apoptotic genes and down-regulation of axono- and neurogenesis in the periinfarct area are likely to account for poor neurorehabilitation after stroke in old rats.

We used proteomics to identify regulated proteins following cerebral ischemia in a rat model. Young rats were subjected to reversible middle cerebral artery (MCA) occlusion and proteins were extracted from the peri-infarcted and the corresponding contralateral area at days 3 and 14 postischemia. Proteins were analyzed by two-dimensional polyacrylamide gel electrophoresis followed by mass spectrometry. We report for the first time that an isoform of annexin A3 (ANXA3) was among the upregulated proteins in the postischemic rat brain. The results were confirmed by real-time PCR and by western blotting. Double- and triple-immunostaining with neuronal and microglia/macrophagic markers demonstrated that ANXA3 is produced by resting microglia in control tissue and by activated microglial/macrophage cells in the infarcted area. 3D-images of the infarcted area suggest that ANXA3 is associated with a phagocytic phenotype. Our study identifies ANXA3 as a novel marker of brain microglia, which should be of substantial value in future studies of microglial cells and its role in the postischemic brain.

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