Permanent focal brain ischemia induces isoform-dependent changes in the pattern of Na+/Ca2+ exchanger gene expression in the ischemic core, periinfarct area, and intact brain regions.
Dysregulation of sodium [Na+]i and calcium [Ca2+]i homeostasis plays a pivotal role in the pathophysiology of cerebral ischemia. Three gene products of the sodium-calcium exchanger family NCX1, NCX2, and NCX3 couple, in a bidirectional way, the movement of these ions across the cell membrane during cerebral ischemia. Each isoform displays a selective distribution in the rat brain. To determine whether NCX gene expression can be regulated after cerebral ischemia, we used NCX isoform-specific antisense radiolabeled probes to analyze, by radioactive in situ hybridization histochemistry, the pattern of NCX1, NCX2, and NCX3 transcripts in the ischemic core, periinfarct area, as well as in nonischemic brain regions, after 6 and 24 h of permanent middle cerebral artery occlusion (pMCAO) in rats. We found that in the focal region, comprising divisions of the prefrontal, somatosensory, and insular cortices, all three NCX transcripts were downregulated. In the periinfarct area, comprising part of the motor cortex and the lateral compartments of the caudate-putamen, NCX2 messenger ribonucleic acid (mRNA) was downregulated, whereas NCX3 mRNA was significantly upregulated. In remote nonischemic brain regions such as the prelimbic and infralimbic cortices, and tenia tecta, both NCX1 and NCX3 transcripts were upregulated, whereas in the medial caudate-putamen only NCX3 transcripts increased. In all these intact regions, NCX2 signal strongly decreased. These results indicate that NCX gene expression is regulated after pMCAO in a differential manner, depending on the exchanger isoform and region involved in the insult. These data may provide a better understanding of each NCX subtype's pathophysiologic role and may allow researchers to design appropriate pharmacological strategies to treat brain ischemia.
Boscia
Francesca
F
Division of Pharmacology, Department of Neuroscience, School of Medicine, University of Naples Federico II, Naples, Italy.
Gala
Rosaria
R
Pignataro
Giuseppe
G
de Bartolomeis
Andrea
A
Cicale
Maria
M
Ambesi-Impiombato
Alberto
A
Di Renzo
Gianfranco
G
Annunziato
Lucio
L
D000818:Animals; D001923:Brain Chemistry; D002545:Brain Ischemia / Q000378:metabolism*; D005786:Gene Expression Regulation; D017403:In Situ Hybridization; D020244:Infarction, Middle Cerebral Artery; D008297:Male; D026901:Membrane Transport Proteins; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D019831:Sodium-Calcium Exchanger / Q000235:genetics*
D026901:Membrane Transport Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; C110927:Slc8a2 protein, rat; C491102:Slc8a3 protein, rat; D019831:Sodium-Calcium Exchanger; C074530:potassium-dependent sodium-calcium exchanger