PUTRESCINE-MODIFIED CATALASE WITH PRESERVED ENZYMATIC-ACTIVITY EXHIBITS INCREASED PERMEABILITY AT THE BLOOD-NERVE AND BLOOD-BRAIN BARRIERS

Much evidence exists in support of the hypothesis that free radicals c ontribute to the pathogenesis of several neurodegenerative disorders a nd that mechanisms of free radical generation occur both intracellular ly and extracellularly. Previous studies in this laboratory have shown that covalent modification of growth factors and antioxidant enzymes with the naturally occurring polyamine, putrescine, increases their pe rmeability at the blood-nerve and blood-brain barriers (BNB and BBB), but does not significantly inhibit bioactivity. Furthermore, putrescin e-modified superoxide dismutase (SOD) was shown to reduce neurodegener ation in a rat model of global cerebral ischemia. The purpose of the p resent study was to modify the antioxidant enzyme, catalase (CAT), wit h putrescine (PUT) at carboxylic acid groups whose ionization, and hen ce reactivity, was controlled with pH and investigate the effects on p ermeability and enzymatic activity. Modification of CAT with PUT incre ased its permeability 2-3-fold and preserved 67% of its enzymatic acti vity compared to native CAT and 137% compared to lyophilized CAT. The results of this study indicate that modification of CAT with putrescin e increases its permeability while preserving enzymatic activity. PUT- SOD administered in combination with PUT-CAT may eliminate both the su peroxide radical and the H2O2 produced from the dismutation of superox ide, respectively, and thus prevent the formation of hydroxyl radicals . This combination may exhibit increased neuroprotective effects, comp ared to native enzymes, following systemic administration for the trea tment of free radical associated neurodegenerative disorders. (C) 1997 Elsevier Science B.V.