Abstract
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.
Highlights
Parkinson’s disease (PD) is a common chronic neurodegenerative disorder characterized by the clinical presentation of motor and nonmotor symptoms
This scenario is supported by observations of graft-induced dyskinesia (GID) responding to systemic administration of low doses of 5-HT1A agonists [10], while L-DOPA-induced dyskinesia (LID) responding to large bolus doses of the same drug aim for a more complete block of the concentrated 5-HT neuronal release of neurotransmitters [14]
The occurrence of GIDs is a serious adverse reaction of striatal transplantation with fetal ventral mesencephalic (VM) tissue in patients with PD hindering the development of future cell replacement therapies
Summary
Human trials with fetal VM transplantation for PD have been conducted over the past two decades on the basis of the hypothesis that if PD is caused by degeneration of the nigrostriatal DA pathway and loss of DA innervation in the striatum, restoration of the lost DA neurons by transplantation could reverse the loss of motor function. Some of the PD patients who underwent transplantation showed remarkable improvement of their motor symptoms, many of them had severe adverse reactions consisting of developing troublesome involuntary movements when off their DA drugs, called off-phase, graft-induced dyskinesias (GIDs) [4,5,6]. Whilst the exact mechanisms underlying the development of GIDs have remained unknown and there has been no effective treatment, proposed theories have been subject to extensive debate
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