Dopamine agonist cabergoline inhibits levodopa-induced caspase activation in 6-OHDA-lesioned mice

Levodopa therapy is the gold standard for symptomatic treatment of Parkinson's disease (PD), but levodopa and/or dopamine (DA)-induced neurotoxicity have been reported in both in vitro and in vivo experimental studies. To clarify the beneficial effects of combining DA agonists with levodopa in PD, the present study examines the effects of cabergoline, a DA agonist, on the levodopa-induced abnormal increase of lipid peroxidation (LPO) and caspase activities in 6-hydroxydopamine (6-OHDA)-lesioned mice. Daily treatments of levodopa/carbidopa for 7 days beginning at 1 day after 6-OHDA i.c.v. injection increased striatal DA levels and glutathione (GSH) contents. Furthermore, a high dose of levodopa/carbidopa (50/12.5 mg/kg) enhanced LPO and caspase-3, -8, and -9 activities in 6-OHDA-lesioned mouse brain. However, when levodopa/carbidopa (50/12.5 mg/kg) was combined with cabergoline (0.25 mg/kg), the effect reduced levodopa's enhancement of caspase-3, -8, and -9 activities in the 6-OHDA-lesioned mouse brain. In addition, the GSH-increasing effect of the combined cabergoline and levodopa/carbidopa treatment was stronger than that of the levodopa/carbidopa mono-treatment. Moreover, cabergoline prevented levodopa-induced abnormal increases of LPO in 6-OHDA-lesioned mice. These results indicate that such prevention is attributable mainly to the increase in GSH content and to the inhibition of caspase activities in 6-OHDA-lesioned mice.