title: Developmental up-regulation of MnSOD in rat oligodendrocytes confers protection against oxidative injury.
abstract: Periventricular leukomalacia, the predominant pathological lesion underlying cerebral palsy in premature infants, is thought to be the result of hypoxic-ischemic injury to the cerebral white matter. The main cell type injured is the developing oligodendrocyte (OL), which has been shown to be more sensitive than mature OLs to both excitotoxic and oxidative mechanisms of injury. A maturation dependence of OL vulnerability to cystine deprivation-induced glutathione depletion has been previously demonstrated in culture. We hypothesized that mitochondria could be involved in this toxicity by generating superoxide and that increased superoxide dismutase (SOD) activity in mature OLs may account for their greater resistance. Cystine deprivation toxicity was found to be associated with mitochondrial dysfunction and intracellular superoxide accumulation in developing OLs. CuZnSOD protein expression and enzyme activity was similar along the OL lineage. In contrast, MnSOD was up-regulated in mature OLs, as manifested by a 53% increase in its expression and a four-fold increase in its activity. Overexpressing MnSOD in developing OLs was associated with a protective effect on mitochondrial membrane potential and a decrease in cell death induced by mild cystine deprivation. The greater challenge presented by total cystine deprivation was resistant to MnSOD overexpression and appeared to be related to hydrogen peroxide toxicity. These data suggest a primary involvement of superoxide in glutathione depletion toxicity in developing OLs, and suggest an important role for MnSOD in the resistance observed in mature OLs.
authors.affiliation: Department of Neurology, Children's Hospital and Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA.
authors.forename: Olivier
authors.initials: O
authors.lastname: Baud
authors.forename: Robin F
authors.initials: RF
authors.lastname: Haynes
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Folkerth
authors.forename: Jianrong
authors.initials: J
authors.lastname: Li
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Volpe
authors.forename: Paul A
authors.initials: PA
authors.lastname: Rosenberg
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology; D001562:Benzimidazoles / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D002232:Carbocyanines / Q000378:metabolism; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000201:enzymology; D003545:Cysteine / Q000172:deficiency / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005609:Free Radicals / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D007239:Infections; D042541:Intracellular Space / Q000187:drug effects / Q000201:enzymology; D007476:Ionophores / Q000494:pharmacology; D008164:Luminescent Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D004676:Myelin Basic Protein / Q000378:metabolism; D019081:O Antigens / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D001562:Benzimidazoles; D002232:Carbocyanines; D005609:Free Radicals; D007476:Ionophores; D008164:Luminescent Proteins; D004676:Myelin Basic Protein; D019081:O Antigens; C111472:mitotracker green FM; D049452:Green Fluorescent Proteins; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D002374:Catalase; D013482:Superoxide Dismutase; D003545:Cysteine