INACTIVATION OF PROTEASE NEXIN-1 BY XANTHINE OXIDASE-DERIVED FREE-RADICALS

Neuronal viability is affected by reactive oxygen species. Lipid perox idation is often defined as a major reason for cellular breakdown. Add itionally, certain indispensable proteins are possible targets for exc essively formed reactive oxygen species. Evidence is given here that p rotease nexin-1 (PN-1), an enchogenous thrombin inhibitor and neurite outgrowth promoter, is inactivated by xanthine oxidase-derived free ra dicals. Varying protection by superoxide dismutase and catalase was ob served, depending on the reaction conditions. The water-soluble alpha- tocopherol analogues MDL 74,406 ,4-dihydro-6-hydroxy-N,N,N2,5,7,8-hept amethyl-2H-1 -benzopyran-2-ethanaminium 4-methylbenzenesulfonate), MDL 74,180DA (2,3-dihydro-2,2,4,6,7-pentamethyl-3-(4-methy dihydro-chlori de) and trolox also protected PN-1. Neurodegeneration may be triggered by oxidative inactivation of protease inhibitors such as PN-1. Protec tion of PN-1 in Alzheimer's or Parkinson's diseases, could be a possib le target for a therapeutic function of antioxidants in these diseases .