Whereas dopamine agonists are known to provide symptomatic benefits for Parkinson's disease, recent clinical trials suggest that they might also be neuroprotective. Laboratory studies demonstrate that dopamine agonists can provide neuroprotective effects in a number of model systems, but the role of receptor-mediated signalling in these effects is controversial. We find that dopamine agonists have robust, concentration-dependent anti-apoptotic activity in PC12 cells that stably express human D2L receptors from cell death due to H2O2 or trophic withdrawal and that the protective effects are abolished in the presence of D2-receptor antagonists. D2 agonists are also neuroprotective in the nigral dopamine cell line SN4741, which express endogenous D2 receptors, whereas no anti-apoptotic activity is observed in native PC12 cells, which do not express detectable D2 receptors. Notably, the agonists studied differ in their relative efficacy to mediate anti-apoptotic effects and in their capacity to stimulate [35S]guanosine 5′-[γ-thio]triphosphate ([35S]GTP[S]) binding, an indicator of G-protein activation. Studies with inhibitors of phosphoinositide 3-kinase (PI 3-kinase), extracellular-signal-regulated kinase or p38 mitogen-activated protein kinase indicate that the PI 3-kinase pathway is required for D2 receptor-mediated cell survival. These studies indicate that certain dopamine agonists can complex with D2 receptors to preferentially transactivate neuroprotective signalling pathways and to mediate increased cell survival.

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