The potassium channel opener (-)-cromakalim prevents glutamate-induced cell death in hippocampal neurons.
(-)-Cromakalim, a typical K+-channel opener, prevents neuronal death induced by either glucose and oxygen privation or by high (100 microM) extracellular glutamate in primary cultures of hippocampus. (-)-Cromakalim has no effect on the earliest events associated with exposure to glutamate. It does not prevent the rapid rise of intracellular Ca2+, the initial swelling of neurons, or the induction of c-fos mRNA transcription. (-)-Cromakalim inhibits all delayed effects associated with the excitotoxic effect of glutamate: (a) (-)-cromakalim inhibits the late and major phase of intracellular Ca2+ increase occurring up to hours after glutamate application; and (b) although (-)-cromakalim cannot prevent the initial cellular swelling induced by glutamate, cells that have been pretreated with (-)-cromakalim return to their original size in a few hours, whereas non-(-)-cromakalim-treated cells remain swollen for more prolonged periods. Many neurons surviving the initial necrotic phase of glutamate-induced cell death undergo progressive DNA cleavage leading to apoptosis. This apoptotic process is prevented completely by (-)-cromakalim. Glibenclamide, a potent blocker of the ATP-sensitive K+ channel, abolishes all the beneficial effects of (-)-cromakalim. These findings strongly suggest that (-)-cromakalim has postsynaptic effects that are closely related to the regulation of Ca2+ homeostasis and cell volume.
Lauritzen
I
I
Institut de Pharmacologie Moléculaire et Cellulaire, CNRS, Sophia Antipolis, Valbonne, France.
De Weille
J R
JR
Lazdunski
M
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D019806:Cromakalim / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology*; D005905:Glyburide / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D009336:Necrosis; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009994:Osmolar Concentration; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
D026902:Potassium Channel Blockers; D015221:Potassium Channels; D019806:Cromakalim; D018698:Glutamic Acid; D005905:Glyburide; D002118:Calcium