Communicated by Jean-Marie Lehn, June 1, 1993 (received for review March 8, 1993) ABSTRACT Transient global forebrain ischemia induces in rat brain a large increase 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 amyloid ,-protein precursor including the Kunitz-type protease-inhibitor domain. At 24 hr after ischemia, this increased expression is particularly observed in regions that are vulnerable to the deleterious effects of ischemia, such as pyramidal cells of the CAl field in the hippocampus. In an attempt to find conditions which prevent the deleterious effects of ischemia, representatives of three different classes of K+ channel openers, (-)-cromakalim, nicorandil, and pinacidil, were administered both before ischemia and during the reperfusion period. This treatment totally blocked the ischemia-induced expression of the different genes. In addition it markedly protected neuronal cells against degeneration. The mechanism of the neuroprotective effects involves the opening of ATP-sensitive K+ channels since glipizide, a specific blocker of that type of channel, abolished the beneficial effects of K+ channel openers. The various classes of K+ channel openers seem to deserve attention as potential drugs for cerebral ischemia.Global forebrain ischemia leads to a complete neuronal death in the CAl field of the hippocampus after 7 days of recovery, whereas the adjacent CA3 sector and the dentate gyrus are largely more resistant (1, 2). The main factors involved in the damage of neuronal tissue following ischemia are ATP depletion (3), intracellular acidosis (4), enhanced release and/or diminished reuptake of the excitatory transmitters glutamate and aspartate (5), generation of free radicals (6), and increased Ca2+ influx and K+ efflux (7,8).N-Methyl-D-aspartate (NMDA) antagonists and Ca2+ channel blockers have exhibited little ability to reduce tissue damage in animals with global ischemia (7, 9). They seem to be more helpful in focal ischemia (10,11 were administered intracerebroventricularly 30 min before the induction of cerebral ischemia and once each day during the recovery period. These doses of KCOs are similar to those previously shown to prevent seizures (31). Glipizide (1 ttmol/5 ul; Pfizer Diagnostics) was injected intracerebroventricularly 20 min prior to openers. Control experiments were performed with intracerebroventricular injection of 0.9% NaCl under conditions used for openers.Cerebral Ischemia Model. Forebrain ischemia involved occlusion of all four major extracranial arteries ("four-vessel occlusion" model) (2).The first day, the rats were anesthesized by inhalation of 2% halothane mixed with 30% oxygen/70% nitrous oxide. Body temperature was maintained at 37°C. The vertebral arteries were irreversibly occluded by electrocoagulation. After a delay of 1 day for recovery, both common carotid arteries were clamped during 20 min in awake and spontaneously ventilating animals. Rats lost their righting refle...

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