valinomycin and Brain-Ischemia

Zinc is concentrated in certain CNS excitatory tracts, especially in hippocampal mossy fibres where it has been suggested to modulate synaptic transmission and plasticity. Using rat mossy fibre synaptosomes depolarized by 4-aminopyridine, we show here that low zinc concentrations restore the membrane potential and reduce glutamate release. Both effects arose from activation of ATP-sensitive potassium channels (KATP), since they were mimicked by the KATP opener diazoxide and antagonized by the KATP blocker tolbutamide. Using recombinant channels expressed in COS-7 cells, we confirmed that micromolar zinc did activate KATP of the type found in hippocampus. We tested the hypothesis that this action of zinc could be beneficial during an ischaemic challenge by using organotypic hippocampal slice cultures. When zinc was applied at micromolar concentrations during a brief anoxic-hypoglycaemic episode, it significantly attenuated the ensuing neuronal death, whereas chelation of endogenous zinc markedly aggravated cell damage. Protective effect of zinc was mediated through KATP, as was shown by using the opener diazoxide and the blocker tolbutamide. Thus, by activating pre-synaptic KATP channels, zinc protects neurones from hyper-excitation, excessive transmitter release and exitotoxicity, and may thus act as an endogenous neuroprotector in conditions such as epilepsy or stroke.

Topics: 4-Aminopyridine; Animals; Animals, Newborn; Brain Ischemia; Chelating Agents; Chlorocebus aethiops; COS Cells; Drug Interactions; Edetic Acid; Glutamic Acid; Gramicidin; Hippocampus; Ionophores; Luminescent Measurements; Male; Membrane Proteins; Microscopy, Electron; Mossy Fibers, Hippocampal; Organ Culture Techniques; Patch-Clamp Techniques; Potassium Channel Blockers; Potassium Channels; Potassium Chloride; Presynaptic Terminals; Rats; Rats, Wistar; Synaptosomes; Time Factors; Tolbutamide; Transfection; Valinomycin; Zinc