title: Hemoglobin-mediated oxidant damage to the central nervous system requires endogenous ascorbate.
abstract: Hemorrhage within the central nervous system (CNS) may be associated with subsequent development of seizure states or paralysis. Prior investigations indicate that hemoglobin, released from extravasated erythrocytes, may be toxic to the CNS by promoting peroxidation of lipids and inhibition of Na,K-ATPase. These deleterious effects are blocked both in vitro and in vivo by the Fe3+ chelator, desferrioxamine, indicating the involvement of free iron derived from hemoglobin. We now report that the Fe2+ chelator, ferene, also inhibits methemoglobin- and ferric iron-mediated CNS lipid oxidation, reflecting the reduction of Fe3+ by some component of the CNS. This reduction is apparent in the accumulation of the highly chromophoric ferene: Fe2+ chelate after the addition of Fe3+ salts to supernatants of murine brain homogenates. Because large amounts of ascorbic acid occur in mammalian CNS, we suspected that this reducing substance might be responsible. Indeed, the peroxidative effects of hemoglobin and iron on murine brain are blocked by washing of CNS membranes or by preincubation of crude homogenates with ascorbate oxidase. Furthermore, the addition of ascorbate to washed CNS membranes fully restores hemoglobin/iron-driven peroxidation. We conclude that posthemorrhagic CNS dysfunction may stem from damaging redox reactions between hemoglobin iron, ascorbic acid, and oxidizable components of the nervous system.
authors.affiliation: Department of Laboratory Medicine/Pathology, University of Minnesota, Minneapolis 55455.
authors.forename: S M
authors.initials: SM
authors.lastname: Sadrzadeh
authors.forename: J W
authors.initials: JW
authors.lastname: Eaton
mesh_terms: D000818:Animals; D001205:Ascorbic Acid / Q000378:metabolism*; D001921:Brain / Q000187:drug effects*; D002560:Cerebrovascular Circulation; D003676:Deferoxamine / Q000494:pharmacology; D006454:Hemoglobins / Q000633:toxicity*; D006470:Hemorrhage / Q000139:chemically induced*; D008054:Lipid Peroxides / Q000494:pharmacology; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors; D013858:Thiobarbiturates
chemical_list: D006454:Hemoglobins; D008054:Lipid Peroxides; D013858:Thiobarbiturates; D000254:Sodium-Potassium-Exchanging ATPase; D003676:Deferoxamine; C029684:thiobarbituric acid; D001205:Ascorbic Acid