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 substantia nigra suffers an oxidative damage during aging that results in both an increase in carbonyl groups of its total proteins and the oxidative inactivation of tyrosine hydroxylase (TH) enzyme, which are partially reversed by chronic treatment with deprenyl. Different mechanisms may account for this effect, including inhibition of the high-affinity dopamine uptake system. We treated aged rats chronically with nomifensine for 2 months and found some significant effects. Nomifensine treatment significantly increased TH enzyme amount in substantia nigra (39.2%), which was accompanied by a significant increase in TH enzyme activity (47.8%). However, these effects were not observed in the terminal field (striatum). As a further step we quantified the oxidative level of proteins by measuring the number of carbonyl groups coupled either to total proteins or specifically to TH enzyme. The proteins of aged rat substantia nigra showed a significant increase of carbonyl groups following nomifensine treatment. The number of carbonyl groups coupled to nigral TH enzyme also increased in the nomifensine-treated animals. However, this increase was lower than that found in the total homogenate proteins. All these results show that the oxidative damage produced during aging in tyrosine hydroxylase enzyme and total proteins is not reduced by nomifensine treatment. On the contrary, the nomifensine treatment increased the oxidative damage to proteins. These results suggest the capability of deprenyl to induce TH enzyme could be due to inhibition of the high-affinity dopamine uptake system, but its ability to protect against oxidative damage is not produced by this mechanism.