K+ channel openers prevent global ischemia-induced expression of c-fos, c-jun, heat shock protein, and amyloid beta-protein precursor genes and neuronal death in rat hippocampus.

Abstract

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...

Neuroprotective role of ATP-sensitive potassium channels in cerebral ischemia

“…Similar to that observed in cardiac ischemia [55,60,114] , a neuroprotective role of K ATP channels has also been suggested in focal and global ischemia models twenty years ago [115] . K ATP channels in a large number of central neurons remain closed, except under conditions of severe metabolic deprivation, such as anoxia or ischemia (Figure 2).…”

“…Activation of the plasmalemmal K ATP channels hyperpolarizes neurons (Figure 3) and may stabilize the resting membrane potential during ischemic insults and stress [125] , which, in turn, can protect neurons against neuronal damage and neurodegeneration that is caused by anoxic membrane depolarization and excitotoxicity [115,126] . Expression of K ATP channel Figure 3.…”

Protective Preconditioning by Transient Global Ischemia in the Rat: Components of Delayed Injury Progression and Lasting Protection Distinguished by Comparisons of Depolarization Thresholds for Cell Loss at Long Survival Times

“…Mechanisms responsible for the observed depolarization delay remain to be identified. Potentiation of ATP-dependent potassium (K ATP ) channel activity would slow depolarization kinetics and be neuroprotective (Ben-Ari et al, 1990;Heurteaux et al, 1993;Lauritzen et al, 1997;Reshef et al, 1998;Sorimachi and Nowak, 2004;Wind et al, 1997), but this possibility has yet to be directly examined. Altered AMPA receptor subunit expression is debated as a factor in ischemic preconditioning (Sommer and Kiessling, 2002;Tanaka et al, 2002;Yamaguchi et al, 1999), but some evidence indicates that, in apparent contrast to the gerbil, preconditioning in the rat may increase expression of the Ca 2 þ impermeable, rapidly desensitizing GluR2 subunit (Alsbo et al, 2001;Kjøller and Diemer, 2000).…”

La tolérance cérébrale : un choix prometteur vers de nouvelles thérapies contre les maladies neurologiques

“…Un précondition-nement pharmacologique par les activateurs des canaux K ATP ou des récepteurs de type A 1 reproduit une fenêtre de protection identique à celle observée dans la tolérance ischémique ou épileptique, et déclenche un signal de stress conduisant à la synthèse de nombreuses protéines, dont HSP70 (heat shock protein), décrite pour ses effets bénéfiques dans la majorité des modèles de pré-conditionnement [10]. L'inhibition des canaux K ATP ou des récepteurs de type A 1 abolit les effets bénéfiques induits par un p r é c o n d i t i o n n e m e n t ischémique ou épileptique [17], tandis que leur activation en phase aiguë protège les neurones d'une ischémie ou d'une crise épileptique [18]. Les récepteurs A 1 de l'adéno-sine et les canaux K ATP pourraient donc avoir à la fois un rôle de senseur et d'effecteur dans la tolé-rance cérébrale, et l'analyse de leur rôle dans la phase tardive du précon-ditionnement cérébral est aussi compliquée par l'existence potentielle de canaux K ATP mitochondriaux [19].…”