Dopamine D2 receptor-mediated antioxidant and neuroprotective effects of ropinirole, a dopamine agonist

Recent information suggests that free radicals are closely involved in the pathogenesis and/or progression of Parkinson's disease (PD). High-dose levo dopa therapy has been suggested to increase oxidative stress, thereby accel erating the progression of PD. Based on this viewpoint, free radical scaven ging, antioxidant and neuroprotective agents which may prevent the progress ion of PD have recently attracted considerable attention. For example, ergo t derivative dopamine (DA) agonists have been reported to scavenge free rad icals in vitro and show a neuroprotective effect in vivo. Non-ergot DA agon ists have also recently been used in the treatment of PD despite the lack o f substantial evidence for any free radical scavenging activity or antioxid ant activity. The present study was conducted to assess the in vitro free r adical scavenging and antioxidant activities of ropinirole, a non-ergot DA agonist, as well as its glutathione (GSH), catalase and superoxide dismutas e (SOD) activating effects and neuroprotective effect in vivo. Ropinirole s cavenges free radicals and suppresses lipid peroxidation in vitro, but thes e activities are very weak, suggesting that the antioxidant effect of ropin irole observed in vitro may be a minor component of its neuroprotective eff ect in vivo. Administration of ropinirole for 7 days increased GSH, catalas e and SOD activities in the striatum and protected striatal dopaminergic ne urons against 6-hydroxydopamine (6-OHDA) in mice. Pre-treatment with sulpir ide prevented ropinirole from enhancing striatal GSH, catalase and SOD acti vities and abolished the protection of dopaminergic neurons against 6-OHDA. Our findings indicate that activation of GSH, catalase and SOB mediated vi a DA D2 receptors may be the principal mechanism of neuroprotection by ropi nirole. (C) 1999 Elsevier Science B.V. All rights reserved.