title: Characterisation of [123I]iomazenil distribution in a rat model of focal cerebral ischaemia in relation to histopathological findings.
abstract: Iodine-123 labelled iomazenil ([(123)I]IMZ) has been reported to be a useful marker of neuronal viability. The brain distribution of [(123)I]IMZ, however, has not been correlated with the pathophysiological response in detail after an ischaemic insult. To characterise [(123)I]IMZ as a marker of neuronal viability, we compared its brain distribution with cyclooxygenase-2 (COX-2) expression, DNA fragmentation and cellular integrity. [(123)I]IMZ and [(125)I]IMP were injected into rats with focal cerebral ischaemia for the purpose of dual-tracer autoradiography. COX-2 and microtubule-associated protein-2 (MAP-2, a marker of cellular integrity) were immunostained. In situ DNA polymerase-I-dependent dUTP incorporation into damaged DNA was used as an indicator of DNA fragmentation. Lesion to normal ratios (LNRs) for [(123)I]IMP and [(125)I]IMZ were calculated. [(123)I]IMZ accumulation was preserved in several regions with impaired [(123)I]IMP accumulation. COX-2 expression was occasionally observed, whereas neither DNA fragmentation nor MAP-2 denaturation was detected in these regions. DNA fragmentation and impaired MAP-2 immunostaining were observed only in the regions with reduced LNRs for both tracers. The LNR for [(123)I]IMZ was significantly lower in regions with impaired MAP-2 immunostaining (0.120+/-0.152, P<0.0001), in regions positive for dUTP incorporation (0.488+/-0.166, P<0.0001) and in regions positive for COX-2 expression (0.626+/-0.186, P<0.001) than in histologically normal regions (0.784+/-0.213). Thus, neuronal DNA is still intact and cellular integrity is maintained in the ischaemic regions with preserved [(123)I]IMZ accumulation. The impairment of [(123)I]IMZ accumulation precedes DNA fragmentation and denaturation of cellular integrity. These results provide the molecular basis of [(123)I]IMZ distribution.
authors.affiliation: Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo, Japan.
authors.forename: Tomohito
authors.initials: T
authors.lastname: Kaji
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kuge
authors.forename: Chiaki
authors.initials: C
authors.lastname: Yokota
authors.forename: Masafumi
authors.initials: M
authors.lastname: Tagaya
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Inoue
authors.forename: Tohru
authors.initials: T
authors.lastname: Shiga
authors.forename: Kazuo
authors.initials: K
authors.lastname: Minematsu
authors.forename: Nagara
authors.initials: N
authors.lastname: Tamaki
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000000981:diagnostic imaging* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005442:Flumazenil / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes; D008297:Male; D008657:Metabolic Clearance Rate; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D005442:Flumazenil; C063038:iomazenil