Mechanisms of action of pramipexole: Putative neuroprotective effects

The neurodegenerative mechanisms involved in the aetiopathogenesis of Parkinson's disease have yet to be fully elucidated. It seems likely, however, that a major role is played by oxidative stress, related to the generation of free radicals associated with dopamine metabolism and loss of mitochondrial electron transport function. Neurotoxins, arising exogenously and/or endogenously, may also be involved. Evidence that pramipexole, a dopamine D₃-preferring agonist, possesses a neuroprotective potential comes from a number of directions. In studies conducted in vivo, pramipexole protects dopaminergic neurones against the effects of transient forebrain ischaemia, and against the neurotoxic effects of methamphetamine, 3-acetylpyridine, 6-hydroxydopamine and MPTP. In in vitro studies using cultures of rat mesencephalic, human neuroblastoma, rat mesencephalic/murine neuroblastoma-glioma hybrid, or rat cerebellar granule cells, pramipexole has been shown to attenuate the neurotoxic effects of dopamine and the L form of 3,4-dihydroxyphenylalanine (L-DOPA) in neuronal cell culture, as well as of MPP⁺, these effects apparently being linked to pramipexole's antioxidant, free-radical scavenging actions. It has also been demonstrated that D₃ receptor stimulation may be a necessary element in at least part of the neuroprotective action exerted by pramipexole, whilst other studies suggest that pramipexole may enhance trophic activity in dopaminergic cells. It seems likely that the neuroprotective actions of pramipexole involve these different mechanisms (and possibly others) acting in concert. In contrast to the substantial evidence from laboratory studies that pramipexole is able to exert marked neuroprotective effects on dopaminergic neurones, it is not yet clear that such effects form an important part of the therapeutic action of pramipexole when it is used clinically in the treatment of Parkinson's disease. Recent evidence from single photon emission computed tomography (SPECT) imaging studies has revealed a trend towards a reduction in dopaminergic neurodegeneration in patients with early Parkinson's disease treated with pramipexole, relative to effects seen in patients treated for the same period of time with carbidopa/L-DOPA; after approximately 2 years the trend did not attain statistical significance, but patients are being followed up for a further 2 years. Further work is required to establish whether, and to what extent, the neuroprotective actions of pramipexole seen in laboratory-based studies translate into the protection and preservation of nigrostriatal dopaminergic neurones in parkinsonian patients.