Na+/Ca2+ exchanger maintains ionic homeostasis in the peri-infarct area.
OBJECTIVE
A prominent feature of cerebral ischemia is the excessive intracellular accumulation of both Na(+) and Ca(2+) ions, which results in subsequent cell death. The plasma membrane Na(+)/Ca(2+) 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 permanent middle cerebral artery occlusion.


RESULTS
Bepridil, an inhibitor of NCX, reduced in a concentration-dependent manner (IC(50)=68 micromol/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) (IC(50)=6 micromol/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.
Tortiglione
Anna
A
Fondazione Santa Lucia IRCCS, CERC, Rome, Italy.
Picconi
Barbara
B
Barone
Ilaria
I
Centonze
Diego
D
Rossi
Silvia
S
Costa
Cinzia
C
Di Filippo
Massimiliano
M
Tozzi
Alessandro
A
Tantucci
Michela
M
Bernardi
Giorgio
G
Annunziato
Lucio
L
Calabresi
Paolo
P
D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology*; D006706:Homeostasis; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology*; D007477:Ions / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D019831:Sodium-Calcium Exchanger / Q000502:physiology*
D007477:Ions; D019831:Sodium-Calcium Exchanger