title: Intracerebral transportation and cellular localisation of insulin-like growth factor-1 following central administration to rats with hypoxic-ischemic brain injury.
abstract: Insulin-like growth factor-1 (IGF-1) has been shown to be neuroprotective when administered centrally following hypoxic-ischemic (HI) brain injury. However, the cerebral distribution and site of action of IGF-1 after intracerebroventricular (i.c.v.) administration are not known. A unilateral HI brain injury was induced in adult rats by a modified Levine method. Either 3H-IGF-1 alone, or in combination with unlabelled IGF-1, was administered into the lateral ventricle 2 h after injury. The activity of 3H-IGF-1 signal in the potentially injured cortex was compared between two treatment groups using image analysis. The regional distribution and cellular localisation of 3H-IGF-1 were examined autoradiographically in potentially injured hemispheres at 0.5 and 6 h after administration. Tritiated IGF-1 was detected predominantly in the pia mater, perivascular spaces and subcortical white matter tracts 0.5 h after administration and decreased by 6 h (p<0.05). The signals associated with the perivascular spaces and pia mater were not blocked by unlabelled IGF-1, suggesting non-saturable binding in these brain areas. IGF-1 signal was co-localised with IGF binding protein (IGFBP)-2 immunostaining in the white matter tracts where the signal was blocked by unlabelled IGF-1, suggesting competitive association. IGF-1 signal associated with neurons and glia was maximal in the cerebral cortex and less in the CA1-2 subregion of the hippocampus which were blocked by unlabelled IGF-1 (p<0.05). The signals from cortical neurons did not decrease 6 h after administration, suggesting specific and persistent binding to these cells. Our results indicate that centrally administered IGF-1 can be translocated to neurons and glia via the perivascular circulation and the ependymal cell-white matter tract pathways.
authors.affiliation: Research Centre for Developmental Medicine and Biology, School of Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand. j.guan@auckland.ac.nz
authors.forename: J
authors.initials: J
authors.lastname: Guan
authors.forename: E J
authors.initials: EJ
authors.lastname: Beilharz
authors.forename: S J
authors.initials: SJ
authors.lastname: Skinner
authors.forename: C E
authors.initials: CE
authors.lastname: Williams
authors.forename: P D
authors.initials: PD
authors.lastname: Gluckman
mesh_terms: D000818:Animals; D001345:Autoradiography; D001692:Biological Transport / Q000187:drug effects; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism*; D007150:Immunohistochemistry; D007276:Injections, Intraventricular; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D008297:Male; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D014316:Tritium
chemical_list: D018971:Insulin-Like Growth Factor Binding Protein 2; D014316:Tritium; D007334:Insulin-Like Growth Factor I