Quantitative analysis of cell death and ferritin expression in response to cortical iron: implications for hypoxia-ischemia and stroke.
Iron that is not bound to storage proteins can catalyse the generation of toxic hydroxyl radicals. Iron can be released from brain storage proteins by hypoxic conditions, such as those that accompany stroke, and the situation can be compounded by iron released from hemoglobin in extravasated blood cells. Despite the neurotoxicity of iron, there is little quantitative data concerning the spatio-temporal extent of its toxicity in vivo. The present study measures the effects of a pathologically relevant concentration of iron (1.0 mM) on neuronal death and on ferritin expression in vivo. Injection of iron (1 microl ferric ammonium citrate) into rat parietal cortex resulted in 7.9-fold more ferritin-labeled cells than did control injections of ammonium citrate at 1 day post-injection. This elevated expression continued for at least 1 week. One day after injection, the mean number of Fluoro-Jade-labeled degenerating neurons in 100 microm sections passing through the center of ferric ammonium citrate injection sites was 664+/-64. This value was 4.5-fold higher than at ammonium citrate injection sites, and this difference increased to 56-fold by day three. By 5 days post-injection, few dying neurons were observed at the control sites, but neurodegeneration continued beyond a week at the iron-injected sites. Thus, iron released during a brief episode of hypoxia-ischemia or during a stroke may be neurotoxic for a protracted period. Therefore, our findings indicate that it may be beneficial to target iron-induced peroxidation throughout the first few weeks following an intracerebral hemorrhage or an hypoxic-ischemic episode.
Bishop
G M
GM
Department of Psychology, Monash University, Clayton, VIC 3800, Australia. glenda.bishop@sci.monash.edu.au
Robinson
S R
SR
D000818:Animals; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia; D005260:Female; D005290:Ferric Compounds / Q000494:pharmacology / Q000633:toxicity; D005293:Ferritins / Q000096:biosynthesis* / Q000235:genetics; D005452:Fluoresceins; D005456:Fluorescent Dyes; D005609:Free Radicals; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism*; D007424:Intracellular Fluid / Q000737:chemistry; D007501:Iron / Q000032:analysis / Q000494:pharmacology / Q000633:toxicity*; D008262:Macrophage Activation / Q000187:drug effects; D017628:Microglia / Q000187:drug effects; D008845:Microinjections; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000737:chemistry / Q000187:drug effects / Q000648:ultrastructure; D009930:Organic Chemicals; D010296:Parietal Lobe / Q000187:drug effects* / Q000378:metabolism; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000378:metabolism*; D013997:Time Factors
D005290:Ferric Compounds; D005452:Fluoresceins; D005456:Fluorescent Dyes; D005609:Free Radicals; D009419:Nerve Tissue Proteins; D009930:Organic Chemicals; D000644:Quaternary Ammonium Compounds; C435731:fluoro jade; D005293:Ferritins; D007501:Iron; C013531:ferric ammonium citrate