Dopamine Agonists Versus Precursors—Which are Neuroprotective?
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A growing body of evidence suggests that in addition to ameliorating the symptoms of Parkinson's disease (PD), dopamine agonists or precursors may actually affect the degeneration of dopaminergic neurons. In yesterday's Journal of the American Medical Association, a report from the Parkinson Study Group supports this contention.
The group, steered by committee chair Kenneth Marek of the Institute for Neurodegenerative Disorders, New Haven, Connecticut, has followed progression of PD in 67 patients who began treatment four years ago with either the dopamine precursor levodopa, or the receptor agonist pramipexole. The researchers followed neurodegeneration by measuring levels of dopamine transporter, widely considered to reflect accurately the number of active dopaminergic neurons (see accompanying commentary) with single-photon emission computed tomography (SPECT) and an I123-tagged transporter-binding tropane analogue.
The patients who started on pramipexole faired better than those who began their treatment with levodopa. After four years the tropane uptake in the striatum of the levodopa group was down by 26 percent as compared to 16 percent in the pramipexole group. Similar differences emerged after 34 months (loss of 20 versus 11 percent) or 22 months (13 versus 7 percent) of treatment. Furthermore, patients who started treatment with pramipexole but needed supplemental levodopa treatment after 22 months continued to exhibit a smaller reduction in transporter loss.
Unfortunately the study did not incorporate a placebo group, so whether the differences are due to accelerated loss in the levodopa group or decelerated loss in the pramipexole group is debatable. The authors favor the latter scenario based on published data indicating that receptor agonists may be neuroprotective. The study also suggests a correlation between the imaging data and severity of symptoms, but the authors are cautious to draw any strong conclusions partly because the course of symptoms is difficult to measure while patients are on medication.—Tom Fagan
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Primary Papers
- Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression. JAMA. 2002 Apr 3;287(13):1653-61. PubMed.
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Comments
This is an interesting manuscript that asks whether two different classes of anti-parkinsonian drugs (the dopamine precursor L-DOPA, and the D2/D3 dopamine receptor agonist pramipexole) differentially affect dopamine neuron viability over the course of 4
years, as detected by the SPECT ligand CIT. CIT and other tropane analogs bind to the dopamine transporter, a protein localized almost exclusively on dopamine neurons. The conclusions drawn are that early intervention with pramipexole is more effective than L-DOPA in retarding dopamine neuronal degeneration. The tantalizing conclusions support the view that specific anti-Parkinsonian drugs may "protect" dopamine neurons from further degeneration.
The conclusions require some tempering because, although the transporter is an effective marker of dopamine neurons, it is increasingly recognized that the transporter can be regulated. That is, the transporter may up- and down-regulate and traffic top the interior of the cell in response to substrates and antagonists. Accordingly, it is not clear whether the findings reflect neuroprotection or a regulated transporter.
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