Hemoglobin and iron-evoked oxidative stress in the brain: protection by bile pigments, manganese and S-nitrosoglutathione.
In the present in vitro and in vivo study we investigated the pro-oxidant effects of hemoglobin, as well as the antioxidant effects of its metabolites, in the brain. Incubation of rat brain homogenates with hemoglobin (0-10 microM) but not hemin induced lipid peroxidation up to 24 h (EC50 = 1.2 microM). Hemoglobin's effects were similar to ferrous ion (EC50 = 1.7 microM) and were blocked by the chelating agent deferoxamine (IC50 0.5 microM) and a nitric oxide-releasing compound S-nitrosoglutathione (IC50 = 40 microM). However, metabolites of hemoglobin - biliverdin and bilirubin - inhibited brain lipid peroxidation induced by cell disruption and hemoglobin (biliverdin IC50 = 12-30 and bilirubin IC50 = 75-170 microM). Biliverdin's antioxidative effects in spontaneous and iron-evoked lipid peroxidation were further augmented by manganese (2 microM) since manganese is an antioxidative transition metal and conjugates with bile pigments. Intrastriatal infusion of hemoglobin (0-24 nmol) produced slight, but significant 20-22% decreases in striatal dopamine levels. Whereas, intrastriatal infusion of ferrous citrate (0-24 nmol) dose-dependently induced a greater 66% depletion of striatal dopamine which was preceded by an acute increase of lipid peroxidation. In conclusion, contrary to the in vitro results hemoglobin is far less neurotoxic than ferrous ions in the brain. It is speculated that hemoglobin may be partially detoxified by heme oxygenase and biliverdin reductase to its antioxidative metabolites in the brain. However, in head trauma and stroke, massive bleeding could significantly produce iron-mediated oxidative stress and neurodegeneration which could be minimized by endogenous antioxidants such as biliverdin, bilirubin, manganese and S-nitrosoglutathione.
Van Bergen
P
P
Unit on Neurodegeneration and Neuroprotection, Laboratory of Clinical Science, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892-1264, USA.
Rauhala
P
P
Spooner
C M
CM
Chiueh
C C
CC
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001654:Bile Pigments / Q000378:metabolism* / Q000494:pharmacology; D001663:Bilirubin / Q000378:metabolism / Q000494:pharmacology; D001664:Biliverdine / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019343:Citric Acid; D003676:Deferoxamine / Q000494:pharmacology; D005296:Ferrous Compounds / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006454:Hemoglobins / Q000378:metabolism* / Q000494:pharmacology; D007501:Iron / Q000378:metabolism*; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008345:Manganese / Q000378:metabolism* / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009603:Nitroso Compounds / Q000378:metabolism* / Q000494:pharmacology; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D026422:S-Nitrosoglutathione; D014020:Tissue Extracts / Q000378:metabolism
D000975:Antioxidants; D001654:Bile Pigments; D005296:Ferrous Compounds; D006454:Hemoglobins; D009603:Nitroso Compounds; D016877:Oxidants; D014020:Tissue Extracts; D019343:Citric Acid; C016600:ferrous citrate; D008345:Manganese; D026422:S-Nitrosoglutathione; D007501:Iron; D005978:Glutathione; D003676:Deferoxamine; D001664:Biliverdine; D001663:Bilirubin