Exchanger Maintains Ionic Homeostasis in the Peri - Infarct Area

Background and Purpose—A prominent feature of cerebral ischemia is the excessive intracellular accumulation of both Na and Ca ions, which results in subsequent cell death. The plasma membrane Na /Ca 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 mol/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 (CBDMB) (IC50 6 mol/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. (Stroke. 2007;38:000-000.)