Co-Grafts in Dopamine-Depleted Primates: Preliminary Results and Theoretical Issues Related to Human Applications for Parkinson’s Disease
Transplantation of embryonic mesencephalon has been attempted in several hundred Parkinson’s disease patients worldwide. Initial reports support the role of these dopamine-producing grafts in ameliorating some of the signs and symptoms of the disease (Lindvall et al., 1989; Lindvall et al., 1990; Freed et al., 1992; Spencer et al., 1992; Widner et al., 1992). In particular, many patients 1) require less daily levodopa after grafting, 2) have a greater percentage of “on” time, and 3) show reduced dyskinesias. Nevertheless, considerable variation exists in the methodological approach followed by each group of clinical investigators, in part because it is difficult to perform experiments with human neural tissue that would provide unequivocal answers to technical questions about optimal survival parameters for the grafted tissue. For example, a study of the survival rate of grafted human dopamine neurons utilized the rat as a host (Brundin et al, 1988). This investigation found poor (i.e. 2-5%) survival of dopamine neurons, which may be influenced by several factors including the relatively small size of the rat brain. Perhaps, there is insufficient room to permit survival of great numbers of these proportionally larger human neurons in the confines of the rat striatum. Moreover, the role, if any, played by immunosuppression is unclear. As a consequence of this low survival, some clinical experiments have utilized mesencephalic tissue from several embryos in attempts to increase the total number of viable dopamine neurons, but this results in a considerably larger number of grafted non-dopaminergic neurons and the role of these presumably “silent” neurons is unknown. Since these grafts contain substantial numbers of neuroblasts and progenitor cells of the ventral mesencephalon, they presumably could be replete with neuronal and glial representatives of the mesencephalic reticular formation, the red nucleus, the ventral tegmentum, the oculomotor and trochlear nuclei, the proprioceptive nucleus of the trigeminal complex, serotonergic neurons of the dorsal raphe and many others for example. Since we are unaware of the influence that these neurons may exert on the host brain, it might be prudent to limit the potential contribution of this non-dopaminergic constituent of ventral mesencephalic grafts. This suggests that attention should be paid to mechanisms for enhancing the yield of grafted dopamine neurons.
KeywordsDopamine Neuron Ventral Mesencephalon Mesencephalic Tissue Host Striatum Striatal Graft
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