K-INDUCED EXPRESSION OF C-FOS, C-JUN, HEAT-SHOCK PROTEIN, AND AMYLOIDBETA-PROTEIN PRECURSOR GENES AND NEURONAL DEATH IN RAT HIPPOCAMPUS( CHANNEL OPENERS PREVENT GLOBAL ISCHEMIA)

Transient global forebrain ischemia induces in rat brain a large incre ase of expression of the immediate early genes c-fos and c-jun and of the mRNAs for the 70-kDa heat-shock protein and for the form of the am yloid beta-protein precursor including the Kunitz-type protease-inhibi tor domain. At 24 hr after ischemia, this increased expression is part icularly observed in regions that are vulnerable to the deleterious ef fects of ischemia, such as pyramidal cells of the CA1 field in the hip pocampus. In an attempt to find conditions which prevent the deleterio us effects of ischemia, representatives of three different classes of K+ channel openers, (-)-cromakalim, nicorandil, and pinacidil, were ad ministered both before ischemia and during the reperfusion period. Thi s treatment totally blocked the ischemia-induced expression of the dif ferent genes. In addition it markedly protected neuronal cells against degeneration. The mechanism of the neuroprotective effects involves t he opening of ATP-sensitive K+ channels since glipizide, a specific bl ocker of that type of channel, abolished the beneficial effects of Kchannel openers. The various classes of K+ channel openers seem to des erve attention as potential drugs for cerebral ischemia.