Molecular mechanism in activation of glutathione system by ropinirole, a selective dopamine D2 agonist

We have previously reported that ropinirole, a non-ergot dopamine agonist, has neuroprotective effects against 6-hydroxydopamine in mice based on in vivo antioxidant properties such as the glutathione (GSH)-activating effect. In the present study, we determined that the effects of ropinirole on the level of expression of GSH-related enzyme mRNA, these enzymes were shown to regulate GSH contents in the brain. This study focused on the mechanism of GSH enhancement by ropinirole. Striatal GSH contents were significantly increased by 7-day daily administration of ropinirole. Furthermore, the expression levels of gamma-glutamylcysteine synthetase (gamma-GCS), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S-transferase (GST) mRNA increased following daily injections of ropinirole for 7 days. In addition, ropinirole treatment for 7 days suppressed auto-oxidation in mouse striatal homogenates, in contrast to the vehicle treatment. In conclusion, ropinirole was able to suppress auto-oxidation, most probably by increasing GSH levels due to an increase of GSH synthesis. In addition, it is likely that auto-oxidation was also suppressed by the activation of GSH-regulating enzymes such as GPx, GR, and GST in the mouse striatum. Thus, our results indicate that the GSH-activating effect of ropinirole may render this dopamine agonist beneficial as a neuroprotective drug.