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.
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 beta-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 CA1 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.
Heurteaux
C
C
Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France.
Bertaina
V
V
Widmann
C
C
Lazdunski
M
M
D017398:Alternative Splicing; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001578:Benzopyrans / Q000494:pharmacology; D002545:Brain Ischemia / Q000503:physiopathology*; D016923:Cell Death; D019806:Cromakalim; D005786:Gene Expression Regulation / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D006360:Heat-Shock Proteins / Q000235:genetics*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D017403:In Situ Hybridization; D008297:Male; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D020108:Nicorandil; D015345:Oligonucleotide Probes / Q000737:chemistry; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar
D016564:Amyloid beta-Protein Precursor; D001578:Benzopyrans; D006146:Guanidines; D006360:Heat-Shock Proteins; D015345:Oligonucleotide Probes; D015221:Potassium Channels; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D011758:Pyrroles; D012333:RNA, Messenger; D019806:Cromakalim; D009536:Niacinamide; D020108:Nicorandil; D020110:Pinacidil