Hemin toxicity: a preventable source of brain damage following hemorrhagic stroke.
Hemorrhagic stroke is a common cause of permanent brain damage, with a significant amount of the damage occurring in the weeks following a stroke. This secondary damage is partly due to the toxic effects of hemin, a breakdown product of hemoglobin. The serum proteins hemopexin and albumin can bind hemin, but these natural defenses are insufficient to cope with the extremely high amounts of hemin (10 mM) that can potentially be liberated from hemoglobin in a hematoma. The present review discusses how hemin gets into brain cells, and examines the multiple routes through which hemin can be toxic. These include the release of redox-active iron, the depletion of cellular stores of NADPH and glutathione, the production of superoxide and hydroxyl radicals, and the peroxidation of membrane lipids. Important gaps are revealed in contemporary knowledge about the metabolism of hemin by brain cells, particularly regarding how hemin interacts with hydrogen peroxide. Strategies currently being developed for the reduction of hemin toxicity after hemorrhagic stroke include chelation therapy, antioxidant therapy and the modulation of heme oxygenase activity. Future strategies may be directed at preventing the uptake of hemin into brain cells to limit the opportunity for toxic interactions.
Robinson
Stephen R
SR
School of Psychology & Psychiatry, Monash University, Victoria, Australia. stephen.robinson@med.monash.edu.au
Dang
Theresa N
TN
Dringen
Ralf
R
Bishop
Glenda M
GM
D001930:Brain Injuries / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006427:Hemin / Q000633:toxicity*; D006454:Hemoglobins / Q000378:metabolism; D006466:Hemopexin / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D020300:Intracranial Hemorrhages / Q000150:complications* / Q000473:pathology; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D020521:Stroke / Q000150:complications* / Q000473:pathology
D006454:Hemoglobins; D016877:Oxidants; D006427:Hemin; D006466:Hemopexin; D006861:Hydrogen Peroxide; D006419:Heme Oxygenase (Decyclizing)