on March 29, 2007
Published online before print March 29, 2007, doi: 10.1161/STROKEAHA.106.478644
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Submitted on November 24, 2006
From Fondazione Santa Lucia IRCCS (A.T., A.Tozzi, B.P., C.C., D.C., G.B., I.B., P.C.), CERC, Rome, Italy; Clinica Neurologica (D.C., G.B., I.B., S.R.), Dip di Neuroscienze, Università di Roma Tor Vergata, Rome, Italy; Division of Pharmacology (A.T., L.A.), Department of Neuroscience, School of Medicine, "Federico II" University of Naples, Naples, Italy; Clinica Neurologica (A.Tozzi, C.C., M.D.F., M.T., P.C.), Dip Specialità Medico-Chirurgiche, Università di Perugia, Perugia, Italy. * To whom correspondence should be addressed. E-mail: calabre{at}unipg.it.
Background and Purpose--A prominent feature of cerebral ischemia is the excessive intracellular accumulation of both Na+ and Ca2+ ions, which results in subsequent cell death. The plasma membrane Na+/Ca2+ exchanger (NCX), regulates the distribution of these ions acting either in the forward mode or in its reverse mode and it can play a critical role in brain ischemia. However, it is unclear whether the activity of NCX leads to detrimental or beneficial effects. Methods--Extracellular field potentials and whole-cell patch clamp recordings were obtained from rat corticostriatal brain-slice preparations in the peri-infarct area 24 hours after the permanent middle cerebral artery occlusion. Ischemia was induced in rats by permanents middle cerebral artery occlusion. Results--Bepridil, an inhibitor of NCX, reduced in a concentration-dependent manner (IC50=68 µmol/L) the field potential amplitude recorded from the peri-infarct area of corticostriatal slices. Conversely, no change was observed in sham-operated animals. The effect of bepridil was mimicked by 5-(N-4-chlorobenzyl)-2',4'-dimethylbenzamil (CB-DMB) (IC50=6 µmol/L), a more selective inhibitor of NCX. In whole-cell patch clamp experiments, bepridil and CB-DMB caused an inward current in spiny neurons recorded from the peri-infarct area but not in the same cells recorded from controls. Interestingly, cholinergic interneurons recorded from the striatal peri-infarct area did not develop an inward current after the application of NCX inhibitors, suggesting that the electrophysiological alterations induced by NCX inhibition are cell-type specific. Bepridil and CB-DMB also induced a suppression of excitatory synaptic currents in most of spiny neurons recorded from the peri-infarct area. This effect was not coupled to a significant change of paired-pulse facilitation suggesting a postsynaptic site of action. Conclusions--Our data indicate that NCX plays a critical role in the maintenance of ionic homeostasis in the peri-infarct area.
Accepted on December 14, 2006
Na+/Ca2+ Exchanger Maintains Ionic Homeostasis in the Peri-Infarct Area
Anna Tortiglione PhD;
Key words: electrophysiology • field potential • ischemia • Na+/Ca2+ exchanger • permanent middle cerebral artery occlusion • striatum
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