Contusion or cortical laceration causes bleeding within the neuropil, followed by red blood cell hemolysis and deposition of hemoglobin within the neuropil. Iron, liberated from hemoglobin and transferrin and deposited as hemosiderin, is found within the brain of patients with PTE.55 Iron is critical to biological functions, but the two stable oxidation states and the redox properties of iron pose a biological hazard. Oxidation of ferrous iron to ferric is a simple reaction yielding insoluble hydroxide complexes. Autoxidation reactions in aqueous solution, or biological fluids, with or without chelators, causes a complicated series of one-electron transfer reactions yielding free-radical intermediates. Addition of iron salts or heme compounds to solutions containing polyunsaturated fatty acids or to suspensions of subcellular organelles results in the formation of highly reactive free-radical oxidants, including perferryl ions, superoxide radicals, singlet oxygen, and hydroxyl radicals.14,56–59 Although free-radical species may form by iron-catalyzed Haber-Weiss reactions,60,61 these oxidants are also actively generated by iron in biologically chelated forms in heme or with adenosine 5'-diphosphate.57,62
Free radicals react with methylene groups adjacent to double bonds of polyunsaturated fatty acids and lipids within cellular membranes, causing hydrogen abstraction and subsequent propagation of peroxidation reactions.57 This nonenzymatic initiation and propagation of lipid peroxidation disrupts membranes of subcellular organelles, degrades deoxyribose and amino acids, and yields diene conjugates and fluorescent chromophores.63–65 Inorganic iron salts, hematin, and hemoproteins stimulate peroxidation of lipids of microsomes and mitochondria and change cellular thiodisulfide function.66
Alkyl hydroxyl and peroxyl species of fatty acids propagate until a termination reaction occurs with a membrane constituent capable of donating an electron without forming a free radical. Such constituents include tocopherol, cholesterol, proteins, or the sulfhydryl group of glutathione.62,67–69 Pretreatment of animals with a-tocopherol and selenium prevented histopathologic alterations after injection of aqueous iron into neural tissue, further supporting the contention that peroxidative reactions are important in responses to brain injury.67–70
Reviewed and revised April 2004 by Steven C. Schachter, MD, epilepsy.com Editorial Board.
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