Since the 1980 s, when
cell transplantation into the brain as a cure for
Parkinson's disease hit the headlines, several patients with
Parkinson's disease have received
transplantation of cells from aborted fetuses with the aim of replacing the
dopamine cells destroyed by the disease. The results in human studies were unpredictable and raised controversy. Some patients showed remarkable improvement, but many of the patients who underwent
transplantation experienced serious disabling adverse reactions, putting an end to human trials since the late 1990 s. These side effects consisted of patients' developing troublesome involuntary, uncontrolled movements in the absence of dopaminergic medication, so-called off-phase, graft-induced
dyskinesias. Notwithstanding the several mechanisms having been proposed, the pathogenesis of this type of
dyskinesias remained unclear and there was no effective treatment. It has been suggested that graft-induced
dyskinesias could be related to fiber outgrowth from the graft causing increased
dopamine release, that could be related to the failure of grafts to restore a precise distribution of dopaminergic synaptic contacts on host neurons or may also be induced by inflammatory and immune responses around the graft. A recent study, however, hypothesized that an important factor for the development of graft-induced
dyskinesias could include the composition of the cell
suspension and specifically that a high proportion of serotonergic neurons cografted in these transplants engage in nonphysiological properties such as false transmitter release. The findings from this study showed serotonergic hyperinnervation in the grafted striatum of two patients with
Parkinson's disease who exhibited major motor recovery after
transplantation with fetal mesencephalic tissue but later developed graft-induced
dyskinesias. Moreover, the
dyskinesias were significantly attenuated by administration of a
serotonin agonist, which activates the inhibitory
serotonin autoreceptors and attenuates transmitter release from serotonergic neurons, indicating that graft-induced
dyskinesias were caused by the dense serotonergic innervation engaging in false transmitter release. Here the implications of the recent findings for the development of new human trials testing the safety and efficacy of
cell transplantation in patients with
Parkinson's disease are discussed.