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PMID: 8415718 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 90 ·No. 20 ·1993-10-15 ·Pages 9431-5

Heurteaux C, Bertaina V, Widmann C, Lazdunski M

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 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.

MeSH Terms
Alternative Splicing Amyloid beta-Protein Precursor/genetics Animals Base Sequence Benzopyrans/pharmacology Brain Ischemia/physiopathology Cell Death Cromakalim Gene Expression Regulation/drug effects Guanidines/pharmacology Heat-Shock Proteins/genetics Hippocampus/drug effects,metabolism In Situ Hybridization Male Molecular Sequence Data Neurons/cytology Niacinamide/analogs & derivatives,pharmacology Nicorandil Oligonucleotide Probes/chemistry Pinacidil Potassium Channels/drug effects Proto-Oncogene Proteins c-fos/genetics Proto-Oncogene Proteins c-jun/genetics Pyrroles/pharmacology RNA, Messenger/genetics Rats Rats, Wistar
Chemicals
Amyloid beta-Protein Precursor Benzopyrans Guanidines Heat-Shock Proteins Oligonucleotide Probes Potassium Channels Proto-Oncogene Proteins c-fos Proto-Oncogene Proteins c-jun Pyrroles RNA, Messenger Cromakalim Niacinamide Nicorandil Pinacidil
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Heurteaux C
Institut de Pharmacologie Moléculaire et Cellulaire, Valbonne, France.
Bertaina V
Widmann C
Lazdunski M
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.90.20.9431
Published
1993-10-15
Pages
9431-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC47582
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.90.20.9431 PMC Full Text View journal details
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