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キーワード:
Preconditioning; tolerance to ischemia; spreading depression; gene expression; glutamate receptors; nicotinic receptors
要旨:
Preconditioning refers to the adaptative cytoprotection that can be induced by a variety of sublethal insults (e.g. a short period of hypoxia) and which increases the brain resistance to a subsequent, potentially lethal insult (e.g. severe ischemia). This fundamental biological process provides an alternative scientific rationale and strategy for the discovery of effective neuroprotective strategies. Our objective is to identify the biological determinants of increased tolerance through the determination of changes in gene expression and protein profiles at several time points after induction of preconditioning. We are focusing on preconditioning induced by repetitive cortical spreading depression (CSD), because this stimulus allows the preparation of large samples of mouse cortex that are preconditioned evenly and consistently. Differential genomics at time points 1, 3 and 6 h post CSD revealed significant changes in the expression of a large number of genes, among which 178 possible candidates had their expression changed by > 100 folds during this period. A high degree of correlation was found between the 3 time points, indicating good experimental reproducibility, but a further evaluation of the candidate genes is still required. Only a few selected proteins were examined by Western blot analysis, 24 h after CSD. New findings include significant changes in immunoreactivity for the glutamate AMPA receptor GluR1 and GluR2 subunits, and especially a 15-fold increase in that of the a7 nicotinic acetylcholine receptor (a7 nAChR) subunit.
