The potassium channel opener (-)-cromakalim prevents glutamate-induced cell death in hippocampal neurons.

I Lauritzen, J R De Weille, M Lazdunski
Author Information
  1. I Lauritzen: Institut de Pharmacologie Moléculaire et Cellulaire, CNRS, Sophia Antipolis, Valbonne, France.

Abstract

(-)-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.

MeSH Term

Animals
Apoptosis
Calcium
Cell Death
Cells, Cultured
Cromakalim
Glutamic Acid
Glyburide
Hippocampus
Necrosis
Neurons
Osmolar Concentration
Potassium Channel Blockers
Potassium Channels
Rats
Rats, Wistar
Stereoisomerism

Chemicals

Potassium Channel Blockers
Potassium Channels
Cromakalim
Glutamic Acid
Glyburide
Calcium

Word Cloud

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