Inactivation of protease nexin-1 by xanthine oxidase-derived free radicals.
Neuronal viability is affected by reactive oxygen species. Lipid peroxidation is often defined as a major reason for cellular breakdown. Additionally, certain indispensable proteins are possible targets for excessively formed reactive oxygen species. Evidence is given here that protease nexin-1 (PN-1), an endogenous thrombin inhibitor and neurite outgrowth promoter, is inactivated by xanthine oxidase-derived free radicals. Varying protection by superoxide dismutase and catalase was observed, depending on the reaction conditions. The water-soluble alpha-tocopherol analogues MDL 74,406 (R(+)-3,4-dihydro-6-hydroxy-N,N,N-2,5,7,8-heptamethyl-2H-1-benzopy ran-2- ethanaminium 4-methylbenzenesulfonate), MDL 74,180DA (2,3-dihydro-2,2,4,6,7-pentamethyl-3-(4-methyl-piperazino)-1-benzo furan-5-ol dihydro-chloride) and trolox also protected PN-1. Neurodegeneration may be triggered by oxidative inactivation of protease inhibitors such as PN-1. Protection of PN-1 in Alzheimer's or Parkinson's diseases, could be a possible target for a therapeutic function of antioxidants in these diseases.
Bolkenius
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FN
Marion Merrell Dow Research Institute, Strasbourg, France.
Monard
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D016564:Amyloid beta-Protein Precursor; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001921:Brain / Q000201:enzymology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002374:Catalase / Q000494:pharmacology; D016166:Free Radical Scavengers; D009580:Nitroblue Tetrazolium / Q000378:metabolism; D010084:Oxidation-Reduction; D058255:Protease Nexins; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins / Q000378:metabolism; D013482:Superoxide Dismutase / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014527:Uric Acid / Q000378:metabolism; D014810:Vitamin E / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D000975:Antioxidants; D002352:Carrier Proteins; D016166:Free Radical Scavengers; D058255:Protease Nexins; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; D014810:Vitamin E; D014527:Uric Acid; D009580:Nitroblue Tetrazolium; D002374:Catalase; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D013917:Thrombin