Mechanisms of action of pramipexole: Putative neuroprotective effects

The neurodegenerative mechanisms involved in the aetiopathogenesis of Parki nson's disease have yet to be fully elucidated. It seems likely, however, t hat a major role is played by oxidative stress, related to the generation o f free radicals associated with dopamine metabolism and loss of mitochondri al electron transport function. Neurotoxins, arising exogenously and/or end ogenously, may also be involved. Evidence that pramipexole, a dopamine D-3- preferring agonist, possesses a neuroprotective potential comes from a numb er of directions. In studies conducted in vivo, pramipexole protects dopami nergic neurones against the effects of transient forebrain ischaemia, and a gainst the neurotoxic effects of methamphetamine, 3-acetylpyridine, 6-hydro xydopamine and MPTP. In in vitro studies using cultures of rat mesencephali c, human neuroblastoma, rat mesencephalic/murine neuroblastoma-glioma hybri d, or rat cerebellar granule cells, pramipexole has been shown to attenuate the neurotoxic effects of dopamine and the L form of 3,4-dihydroxyphenylal anine (L-DOPA) in neuronal cell culture, as well as of MPP+, these effects apparently being linked to pramipexole's antioxidant, free-radical scavengi ng actions. It has also been demonstrated that D-3 receptor stimulation may be a necessary element in at least part of the neuroprotective action exer ted by pramipexole, whilst other studies suggest that pramipexole may enhan ce trophic activity in dopaminergic cells. It seems likely that the neuropr otective actions of pramipexole involve these different mechanisms (and pos sibly others) acting in concert. In contrast to the substantial evidence fr om laboratory studies that pramipexole is able to exert marked neuroprotect ive 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 f rom single photon emission computed tomography (SPECT) imaging studies has revealed a trend towards a reduction in dopaminergic neurodegeneration in p atients with early Parkinson's disease treated with pramipexole, relative t o effects seen in patients treated for the same period of time with carbido pa/L-DOPA; after approximately 2 years the trend did not attain statistical significance, but patients are being followed up for a further 2 years. Fu rther work is required to establish whether, and to what extent, the neurop rotective actions of pramipexole seen in laboratory-based studies translate into the protection and preservation of nigrostriatal dopaminergic neurone s in parkinsonian patients.