CHRONIC INHIBITION OF THE HIGH-AFFINITY DOPAMINE UPTAKE SYSTEM INCREASES OXIDATIVE DAMAGE TO PROTEINS IN THE AGED RAT SUBSTANTIA-NIGRA

The effect of chronic treatment of aged rats with nomifensine has been studied in the rat nigrostriatal dopaminergic system. The rat substan tia nigra suffers an oxidative damage during aging that results in bot h an increase in carbonyl groups of its total proteins and the oxidati ve inactivation of tyrosine hydroxylase (TH) enzyme,(1) which are part ially reversed by chronic treatment with deprenyl. Different mechanism s may account for this effect, including inhibition of the high-affini ty dopamine uptake system. We treated aged rats chronically with nomif ensine for 2 months and found some significant effects. Nomifensine tr eatment significantly increased TH enzyme amount in substantia nigra ( 39.2%), which was accompanied by a significant increase in TH enzyme a ctivity (47.8%). However, these effects were not observed in the termi nal field (striatum). As a further step we quantified the oxidative le vel of proteins by measuring the number of carbonyl groups coupled eit her to total proteins or specifically to TH enzyme. The proteins of ag ed rat substantia nigra showed a significant increase of carbonyl grou ps following nomifensine treatment. The number of carbonyl groups coup led to nigral TH enzyme also increased in the nomifensine-treated anim als. However, this increase was lower than that found in the total hom ogenate proteins. All these results show that the oxidative damage pro duced during aging in tyrosine hydroxylase enzyme and total proteins i s not reduced by nomifensine treatment. On the contrary, the nomifensi ne treatment increased the oxidative damage to proteins. These results suggest the capability of deprenyl to induce TH enzyme could be due t o inhibition of the high-affinity dopamine uptake system, but its abil ity to protect against oxidative damage is not produced by this mechan ism. (C) 1997 Elsevier Science Inc.