Off-medication dyskinesia is an important and potentially disabling side-effect of transplantation that currently represents a major obstacle to future studies of fetal nigral transplantation and other cell-based therapies in PD. The precise cause of off-medication dyskinesia is not known. Current evidence indicates that levodopa-induced on-medication dyskinesias are related to abnormal intermittent or pulsatile stimulation of denervated dopamine receptors (Obeso et al., 2000). Transplantation of functioning dopamine neurons and terminals might thus be expected to provide dopamine to the striatum in a more continuous and physiologic manner than regular oral formulations of levodopa and so reduce rather than increase the risk of dyskinesia. Indeed,
Lee et al. found a reduction in levodopa-induced dyskinesia following transplantation of dopamine neurons in a rodent model of PD (Lee et al., 2000). However, patchy reinnervation of the striatum or abnormal synaptic connectivity such as could occur with an immune reaction, could lead to regional pul-satility and consequent dyskinesia. Indeed, regional areas of increased FD uptake on PET were observed in one study (Ma et al., 2002). The authors suggested that dopamine released from innervated regions of the striatum or "hot spots" could stimulate upregu-lated, hypersensitive receptors in denervated neighboring areas leading to dyskinesia. In contrast to these findings, PET scans in other transplant studies have not shown inhomogeneities (Olanow et al., 2003), although this does not exclude this possibility.
A variety of other hypotheses have been put forward. Freed et al. proposed that off-medication dyski-nesia might be due to excessive dopamine release from grafts (Freed et al., 2001), but there is no evidence of excess dopaminergic activity on PET or postmortem examination in any of the studies performed to date. Further, we have reported reduced dyskine-sia with survival of larger numbers of implanted dopaminergic neurons (Kordower et al., 1995), and found no correlation between off-medication dyski-nesia and the number of implanted donor cells (Olanow et al., 2003). Hagell et al. suggested that off-medication dyskinesia might relate to long-term storage of cells in tissue culture prior to transplantation, and noted a correlation in their studies with the severity of on-medication dyskinesia at baseline (Hagell et al., 2002). However, in a larger double-blind study, off-medication dyskinesia were observed with freshly transplanted cells that were not cultured and there was no correlation with on-medication dyskinesia scores at baseline or at any other time point during the trial (Olanow et al., 2003). Finally, it has been observed that off-medication dyskinesia resemble diphasic dyskinesia, a form of dyskinesia that is seen with suboptimal dopaminergic levels, and that striatal FD uptake, while increased in comparison to baseline, did not return to the lower limits of normal in any patient (Olanow et al., 2003). These observations suggest that off-medication may be due to partial, but incomplete, reinnervation of the striatum. This hypothesis raises the intriguing possibility that transplantation of increased numbers of functioning dopamine neurons might both enhance efficacy and eliminate off-medication dyskinesia.
Further insight into the cause of off-medication dyskinesia and the development of methods that prevent their occurrence are crucial before studies of fetal nigral transplantation can be resumed in PD patients. It remains uncertain whether this side-effect will prove to be a problem with other cell-based therapies such as stem cells and laboratory studies to assess grafts in animals who have been exposed to levodopa and who experience levodopa-related dyskinesia must be performed prior to commencing clinical trials.
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