Both the Antioxidant and D3 Agonist Actions of Pramipexole Mediate Its Neuroprotective Actions in Mesencephalic Cultures

Pramipexole (PPX) is a full intrinsic activity, direct-acting dopamine (DA) agonist possessing 7-fold higher affinity for D 3 than for D 2 receptors. It also is a potent antioxidant. PPX was previously shown to be neuroprotective because it dose dependently attenuated the DA neuron loss produced by levodopa in mesencephalic cultures. Several different drugs with properties similar to PPX were studied here to better understand the mechanism or mechanisms responsible for this neuroprotective effect. The D 3 -preferring agonist 7-hydroxy-diphenylaminotetralin (7-OH-DPAT) and the D 3 antagonist U99194, respectively, increased and decreased the neuroprotective effects of PPX in a dose-dependent fashion. Addition of the selective D 2 agonist U95666 or the D 2 /D 3 antagonists domperidone or raclopride did not affect PPX’s neuroprotective effect. Interestingly, 7-OH-DPAT by itself did not attenuate the DA neuron loss produced by levodopa. However, when 7-OH-DPAT was combined with a low dose of the antioxidants U101033E or α-tocopherol, the toxic effects of levodopa were attenuated. Similar results were observed when the D 3 -preferring agonist PD128,907 was studied. In addition, media conditioned by exposure of mesencephalic cultures incubated with all D 3 -preferring agonists studied was shown to enhance the growth of DA neurons in freshly harvested recipient cultures implicating a D 3 -mediated trophic activity in the neuroprotective effect. These data suggest that PPX’s neuroprotective actions in the levodopa toxicity model are a consequence of its combined actions as a D 3 receptor agonist and an antioxidant.