| Popis: |
The aim of this project was to advance understanding of the molecular, cellular and genetic mechanisms operating in the microenvironment of grafted embryonic neurons and in particular, to address the question of how enhanced survival and growth of transplanted neurons can be achieved. Descriptive mapping studies were followed by a series of experiments investigating the effect of direct infusion of human recombinant forms of the growth factors: NT4/5, NT3, GDNF, and BDNF on nigral grafts in the 6-OHDA lesioned rat. Neurotrophic factors have been reported to improve survival and growth of embryonic ventral mesencephalic neurons in culture. It was observed that NT4/5 enhanced the functional efficacy of foetal nigral transplants as assessed by metamphetamine-induced rotation, by increasing fibre density within the grafts and fibre outgrowth from the grafted cells into the host striatum. No improved functional or morphological consequences were seen with the other neurotrophic factors in this in vivo model. Studies co-grafting immortalised cell lines transfected with kFGF and embryonic nigral neurons did not show enhanced function, survival or integration of the transplants in the host brain. Finally, reconstruction of the damaged nigrostriatal pathway was attempted using embryonic nigral and bridge grafts of a glial-derived cell line in the 6-OHDA lesioned rat. Amelioration in metamphetamine-induced turning correlated with the number of TH-immunoreactive axons from the midbrain reaching the back of the deafferented striatum and this was highest in the transplanted group with bridge grafts. These experiments highlight a variety of mechanisms operating in the grafted environment which require further elucidation for effective manipulation and use of neural transplantation as a therapy for neurodegenerative disorders. |
