Attempts to increase central dopamine (DA) levels via grafts of pharmacologically relevant tissue provide a viable therapeutic strategy for the treatment of Parkinson's disease. Critical to clinical success is the development of methods whereby grafted DA neuron viability and reinnervation of the host striatum are markedly increased. The survival rate of DA neurons in grafts is estimated to be 5-10%, which suggests that the use of multiple donors may be necessary for enhanced therapeutic benefits. However, an alternate strategy is to increase the survival rate and outgrowth of DA neurons. Tropic and trophic factors derived from striatal neurons and glia aid in nigrostriatal pathway formation and maintenance. Previous evidence suggests that striatal grafts may be used to stimulate neurite extension (tropic effect) of grafted DA neurons. We recently demonstrated that cografted striatal cells also exhibit a trophic effect on grafted DA neurons through increasing DA neuron survival. Since these beneficial effects on DA neuron viability and subsequent neurite outgrowth by striatal cografts may occur by mechanisms similar to those observed in other neural systems in which target cells inhibit programmed cell death (apoptosis), my proposal will attempt to 1) evaluate what effect cocultured striatal cells have on apoptosis in mesencephalic DA neurons in vitro and 2) determine whether striatal cografts exert their trophic effects on grafted mesencephalic DA neurons through the inhibition of apoptosis. The importance of the proposed research lies in the ability to incorporate new technology for the detection of apoptotic cells which should provide insight into mechanisms of DA neuron survival after grafting. My long term objectives are to assess whether striatal cografts can be.
| Sortwell, C E; Blanchard, B C; Collier, T J et al. (1998) Pattern of synaptophysin immunoreactivity within mesencephalic grafts following transplantation in a parkinsonian primate model. Brain Res 791:117-24 |
| Sortwell, C E; Collier, T J; Sladek Jr, J R (1998) Co-grafted embryonic striatum increases the survival of grafted embryonic dopamine neurons. J Comp Neurol 399:530-40 |
