The rat 6-OHDA model is characterized by massive loss of dopaminergic neurons accompanied by obvious motor dysfunction that can be exacerbated by amphetamines. The effects of various treatments on the motor asymmetry can be measured over time and correlated with autopsy findings. For example, in a
detailed study of human fetal dopamine neurons implanted in parkinsonian rats, Clarke et al. showed that the functional effects of the graft were evident only when, as confirmed by serial autopsy histologic studies, they developed dopaminergic synaptic contacts with the host. This occurred at a rather late time points (4-5 months postgrafting), emphasizing again the fact that long-term survival is not sufficient if it is not accompanied by functional connectivity. These results were confirmed by other groups, who extended the studies for up to 2 years posttransplantation. In general, the grafts continue to differentiate and are characterized by abundant TH-positive neurites with many synaptic contacts. The host astroglial reactivity surrounding the graft can be detected and does not appear to be affected by host treatment.
To improve graft survival and integration, Nikkhah et al. developed a microtransplantation technique consisting of multiple small deposits of fewer cells rather than a single large-volume graft. This approach resulted in an increased functional benefit as measured by the significant reduction of rotational asymmetry. Another improvement in the grafting protocol in parkinsonian rats was made by Constantini et al., who showed that cotransplantation of striatal tissues enhanced the benefit of the nigral dopaminergic implants, probably by offering some trophic support. This is an interesting concept and will be further discussed in this article (under trophic factors). Finally, Winkler et al. showed that the efficacy of nigral-striatal cotransplants can be further increased when the striatal grafts are implanted in the host nigra, with the mechanism proposed being a donor-derived, GABA-mediated, inhibitory activity on the host projection neurons.
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