02 Jul 2010

During the late 1980s and the 1990s, tissue grafts, chosen to replace lost dopaminergic neurons, seemed to show great promise for the treatment of Parkinson disease (PD). Yet the results were mixed: Some patients experienced dramatic improvement, but many others developed crippling dyskinesias—jerky, involuntary movements—as a side effect. Now, with new transplantation trials scheduled to start, a paper in the June 30 issue of Science Translational Medicine indicates the worst graft side effects might be avoided by making sure transplants are free of contaminating serotonergic neurons. Surprisingly, researchers led by Marios Politis and Paola Piccini at Imperial College London discovered high levels of these neurons in the grafts of two transplant patients who had developed graft-induced dyskinesias (GIDs). By giving these patients a serotonin receptor agonist, the authors saw a significant reduction in the involuntary movements. Piccini and colleagues suggest that by carefully controlling the purity of transplants, future human trials could be safer and more successful.

The researchers built upon their previous work in which they used positron emission tomography (PET) to non-invasively examine dopamine release in the brains of transplant patients. They determined that GIDs were probably not caused by excessive dopamine release from the grafts (see Piccini et al., 2005). Research on levodopa-induced dyskinesia PD animal models provided a clue to the neurobiology behind the GIDs. Researchers led by Anders Bjorklund at Lund University, Sweden, also a collaborator on the current paper, showed that serotonergic neurons, which are closely related to dopaminergic neurons, convert L-dopa to dopamine in these animals. The serotonergic neurons then release this dopamine haphazardly, contributing to the dyskinesias that developed after L-dopa treatment in the animal models (see Carta et al., 2007 and Carlsson et al., 2007).

To see if a similar mechanism takes place in human transplant patients, Politis and colleagues examined the grafts of two such patients using PET markers specific for dopamine synthesis, dopamine receptors, and serotonin transporters. Both patients had received grafts of ventral mesencephalic tissue from aborted fetuses in the mid-1990s, and both experienced a gradual improvement in their Parkinson’s symptoms over several years. They were able to discontinue L-dopa treatment, but both later developed chronic GIDs in their arms and legs. PET imaging showed that both patients had normal levels of dopamine neurons surviving in their grafts, and normal levels of dopamine synthesis. However, PET imaging showed excessive levels of serotonergic neurons in the grafts of both patients. In particular, the ratio of serotonergic to dopaminergic neurons was two to four times higher than the ratio in normal brains.

The authors hypothesized that the GIDs were caused by the abnormal release of dopamine by serotonergic neurons. They gave each patient three doses of a serotonin receptor agonist, buspirone, at 30-minute intervals, and saw a marked reduction in the dyskinesias for the next four hours (see placebo movie and treatment movie). (Note: Some might find these disturbing.) The patients’ Parkinson’s symptoms did not worsen, and no other side effects were observed.

The results indicate that serotonergic neurons in the grafts are taking up dopamine and releasing it in a dysregulated manner, Politis said. Because serotonergic neurons are not specialized to release dopamine, however, they lack autoregulatory controls, and the swings in dopamine levels that result may cause the dyskinesias, he said. This “false action” of dopamine release by serotonergic neurons possibly occurs when the proportion of serotonergic neurons is high relative to dopaminergic neurons, he suggested.

Politis and colleagues would like to find out how widespread this mechanism is. The next step will be to replicate these findings in other patients, Politis said, because transplant outcomes are quite variable. Because there are only a handful of transplant patients, however, it will be difficult to replicate the results in large numbers.

The authors recommend that future transplant trials with fetal cells should use purer cell populations, by dissecting away serotonergic neurons, and predict that this approach might prevent dyskinesias. If so, this would be a timely finding, as new transplant trials are on the horizon—for example, the TRANSEURO Project is a clinical transplant trial funded by the European Commission, with first surgeries possibly planned for 2012, and involves Lund University in Sweden, Cambridge University and Imperial College London, both in the U.K., among other institutions, and with a second phase planned to include other European and North American centers. Meanwhile, for current transplant patients with dyskinesias, buspirone is not a satisfactory treatment due to its short duration in the body, Politis and colleagues said. They identified a need for pharmaceutical companies to develop longer-acting serotonin agonists to benefit these patients.

Not all scientists agree with the paper’s conclusions. Curt Freed of the University of Colorado Denver in Aurora, whose group has performed over 60 transplants since the 1980s, said, “In our subjects it’s very clear that it’s too much dopamine activity” that causes the dyskinesias. Because dopamine transplants restore the ability to move but cause dyskinesias, exactly as L-dopa treatment does, these transplants “are like an L-dopa infusion, and not like the building of a brain circuit.”

Nonetheless, Freed believes this is an intriguing preliminary study, which may suggest a moderating role for serotonergic neurons in dyskinesias. He would like to see what happens when you give buspirone to people who have dyskinesias but never got a graft. “It could be that this category of drug would be helpful for all people who have drug-induced dyskinesias by its action on all the dopamine neurons in the brain.”—Madolyn Bowman Rogers

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References

Paper Citations

1. Piccini P, Pavese N, Hagell P, Reimer J, Björklund A, Oertel WH, Quinn NP, Brooks DJ, Lindvall O. Factors affecting the clinical outcome after neural transplantation in Parkinson's disease. Brain. 2005 Dec;128(Pt 12):2977-86. PubMed.
2. Carta M, Carlsson T, Kirik D, Björklund A. Dopamine released from 5-HT terminals is the cause of L-DOPA-induced dyskinesia in parkinsonian rats. Brain. 2007 Jul;130(Pt 7):1819-33. PubMed.
3. Carlsson T, Carta M, Winkler C, Björklund A, Kirik D. Serotonin neuron transplants exacerbate L-DOPA-induced dyskinesias in a rat model of Parkinson's disease. J Neurosci. 2007 Jul 25;27(30):8011-22. PubMed.

External Citations

1. placebo movie
2. treatment movie
3. TRANSEURO Project

Further Reading

No Available Further Reading