title: Preferential involvement of Na⁺/Ca²⁺ exchanger type-1 in the brain damage caused by transient focal cerebral ischemia in mice.
abstract: The Na(+)/Ca(2+) exchanger (NCX), an ion-transporter located in the plasma membrane of neuronal cells, contributes to intracellular Ca(2+) homeostasis. Within the brain, three isoforms (NCX1, NCX2, and NCX3) are widely distributed. However, it is not clear to what extent these isoforms are involved in ischemic brain damage in mammals. We therefore used genetically altered mice and isoform-selective NCX inhibitors in a model of transient focal ischemia to investigate the role of each NCX isoform in ischemic brain damage. NCX isoform-mutant mice (NCX1(+/-), NCX2(+/-), and NCX3(+/-)) and wild-type mice were subjected to 90min of middle cerebral artery occlusion (MCAO) followed by 24h of reperfusion. One of three NCX inhibitors [SN-6, KB-R7943, or SEA0400 (3 or 10mgkg(-1), i.p.)] was administered to ddY mice at 30min before more prolonged (4-h) MCAO followed by 24h of reperfusion. After transient MCAO reperfusion, the cerebral infarcts in NCX1(+/-) mice, but not those in NCX2(+/-) or NCX3(+/-) mice, were significantly smaller than those in wild-type mice. SN-6 and SEA0400, which are more selective for the NCX1 isoform, significantly reduced the infarct volume at 10mg/kg. In contrast, KB-R7943, which is more selective for NCX3, did not. These results suggest that the NCX1 isoform may act preferentially (vs. the NCX2 and NCX3 isoforms) to exacerbate the cerebral damage caused by ischemic insult in mice, and that NCX1-selective inhibitors warrant investigation as a potential therapeutic agents for stroke.
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Morimoto
authors.forename: Satomi
authors.initials: S
authors.lastname: Kita
authors.forename: Masamitsu
authors.initials: M
authors.lastname: Shimazawa
authors.forename: Hiroko
authors.initials: H
authors.lastname: Namimatsu
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Tsuruma
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Hayakawa
authors.forename: Kenichi
authors.initials: K
authors.lastname: Mishima
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Egashira
authors.forename: Takuya
authors.initials: T
authors.lastname: Iyoda
authors.forename: Ichiro
authors.initials: I
authors.lastname: Horie
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Gotoh
authors.forename: Katsunori
authors.initials: K
authors.lastname: Iwasaki
authors.forename: Michihiro
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsuda
authors.forename: Akemichi
authors.initials: A
authors.lastname: Baba
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.forename: Kyoji
authors.initials: K
authors.lastname: Horie
authors.forename: Junji
authors.initials: J
authors.lastname: Takeda
authors.forename: Takahiro
authors.initials: T
authors.lastname: Iwamoto
authors.forename: Hideaki
authors.initials: H
authors.lastname: Hara
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D001593:Benzyl Compounds / Q000494:pharmacology; D020520:Brain Infarction / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010647:Phenyl Ethers / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053778:Thiazolidines / Q000494:pharmacology; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; C487681:2-(4-(4-nitrobenzyloxy)benzyl)thiazolidine-4-carboxylic acid ethyl ester; D000814:Aniline Compounds; D001593:Benzyl Compounds; C499849:NCX1 protein, mouse; D010647:Phenyl Ethers; C430918:SEA 0400; C491739:Slc8a2 protein, mouse; C491101:Slc8a3 protein, mouse; D019831:Sodium-Calcium Exchanger; D053778:Thiazolidines; D013890:Thiourea