Toward a restorative therapy for Parkinson´s disease. Studies on the functional efficacy of intracerebral fetal cell transplants and GDNF delivery

Sammanfattning: Parkinson´s disease is characterized by a progressive degeneration of the nigral dopaminergic system. Treatment of disease symptoms using L-DOPA frequently induces side effects such as L-DOPA-induced dyskinesia. New therapeutic approaches are aimed at preventing neurodegeneration or restoring the dopaminergic system by fetal dopaminergic transplants. In this thesis work, we evaluated the neuroprotective capacity of glial cell line-derived neurotrophic factor (GDNF) in the rat Parkinson model. Delayed short-term treatment with glial cell line-derived neurotrophic factor provided long-term rescue of nigral dopaminergic neurons. Nigral administration of GDNF, however, did not prevent the dopaminergic fibre loss in the striatum, and thus, functional recovery was not obtained. We also evaluated the functional efficacy of fetal transplants in the rat Parkinson model. Multiple intrastriatal microtransplants of fetal dopaminergic cells induced pronounced functional improvements. Complete normalization of all cellular and behavioural parameters, however, was not obtained which may be due to the ectopic transplant location. Mulitple intranigral transplants of fetal dopaminergic or fetal GABA-rich striatal tissue also induced improvements of lesion-induced deficits, which are proposed to be due to local intranigral mechanisms. We also characterized a rat model of L-DOPA-induced dyskinesia to show that incidence of dyskinesia, latency to develop dyskinesia, and expression of dyskinesia subtypes depends on the magnitude of striatal dopaminergic denervation. The findings of this thesis have implications for the development of effective new therapies for Parkinson´s disease.