Both the antioxidant and D-3 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 neuroprotec tive 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 mec hanisms responsible for this neuroprotective effect. The D-3-preferring ago nist 7-hydroxy-diphenylaminotetralin (7-OH-DPAT) and the D-3 antagonist U99 194, respectively, increased and decreased the neuroprotective effects of P PX in a dose-dependent fashion. Addition of the selective D-2 agonist U9566 6 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 attenua te the DA neuron loss produced by levodopa. However, when 7-OH-DPAT was com bined with a low dose of the antioxidants U101033E or alpha-tocopherol, the toxic effects of levodopa were attenuated. Similar results were observed w hen the D-3-preferring agonist PD128,907 was studied. In addition, media co nditioned by exposure of mesencephalic cultures incubated with all D-3-pref erring agonists studied was shown to enhance the growth of DA neurons in fr eshly harvested recipient cultures implicating a D-3-mediated trophic activ ity in the neuroprotective effect. These data suggest that PPX's neuroprote ctive actions in the levodopa toxicity model are a consequence of its combi ned actions as a D-3 receptor agonist and an antioxidant.