title: Inhibiting the Na+/H+ exchanger reduces reperfusion injury: a small animal MRI study.
abstract: We used magnetic resonance imaging (MRI) to assess the efficacy of Na+/H+ exchanger isoform 1 (NHE-1) inhibition following cerebral ischemia. Transient focal cerebral ischemia was induced in wild-type controls (NHE-1(+/+)), NHE-1 genetic knockdown mice (NHE-1(+/-)), and NHE-1(+/+) mice treated with the selective NHE-1 inhibitor HOE642. Diffusion weighted imaging (DWI) revealed a brain lesion as early as 1 hour following reperfusion and illustrated significant protection in NHE-1(+/-) mice (16.2 +/- 7.9 mm3 in NHE-1(+/-) mice vs. 47.5 +/- 16.6 mm3 in NHE-1(+/+) mice). Knockdown of NHE-1 showed significantly smaller infarct at 72 hours on T2 imaging (21.2 +/- 12.6 mm3 in NHE-1(+/-) mice vs. 64.6 +/- 2.5 mm3 in NHE-1(+/+) mice). Administration of HOE642 prior to reperfusion or during early reperfusion reduced ischemic damage. Thus, high resolution T2 images can be used for consistent and precise calculation of lesion volumes, while changes of DWI are a sensitive early marker of ischemic injury. The results of this study demonstrate the therapeutic potential for inhibition of NHE-1 in treating cerebral ischemia.
authors.affiliation: Department of Pediatrics, University of Wisconsin, Madison, WI 53792, USA. ferrazzano@pediatrics.wisc.edu
authors.forename: Peter
authors.initials: P
authors.lastname: Ferrazzano
authors.forename: Yejie
authors.initials: Y
authors.lastname: Shi
authors.forename: Namratta
authors.initials: N
authors.lastname: Manhas
authors.forename: Yanping
authors.initials: Y
authors.lastname: Wang
authors.forename: Beth
authors.initials: B
authors.lastname: Hutchinson
authors.forename: Xinzhi
authors.initials: X
authors.lastname: Chen
authors.forename: Vishal
authors.initials: V
authors.lastname: Chanana
authors.forename: Josiah
authors.initials: J
authors.lastname: Gerdts
authors.forename: Mary Elizabeth
authors.initials: ME
authors.lastname: Meyerand
authors.forename: Dandan
authors.initials: D
authors.lastname: Sun
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D038524:Diffusion Magnetic Resonance Imaging; D055785:Gene Knockdown Techniques; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000517:prevention & control*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors*; D018709:Statistics, Nonparametric; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C069139:growth factor-activatable Na-H exchanger NHE-1; C093373:cariporide