Intrastriatal glial cell line-derived neurotrophic factor promotes sprouting of spared nigrostriatal dopaminergic afferents and induces recovery of function in a rat model of Parkinson's disease.

The ability of intrastriatally-administered glial cell line-derived neurotrophic factor to induce reinnervation and functional recovery in the partially-lesioned nigrostriatal dopamine system was explored in rats subjected to an axon terminal lesion induced by injection of 6-hydroxydopamine into the striatum. Glial cell line-derived neurotrophic factor was administered as multiple intrastriatal injections (10 x 5 micrograms) over a three-week period starting four weeks after the 6-hydroxydopamine injection, i.e. at the time when the acute phase of degeneration of the nigral dopamine neurons is complete. In the control group the lesion induced a 75-90% reduction of the dopaminergic innervation in the dorsolateral striatum (assessed by [3H]N-[1-(2-benzo(b)thiopenyl)cyclohexyl]piperidine-labelled dopamine uptake sites), and an approximately 50% reduction in the number of tyrosine hydroxylase-positive cell bodies in the central part of the substantia nigra, accompanied by a significant impairment in spontaneous motor behaviour, as assessed by a forelimb stepping test. In the glial cell line-derived neurotrophic factor-treated animals striatal [3H]N-[1-(2-benzo(b)thiopenyl)cyclohexyl]piperidine binding was restored to 70-95% of normal and contralateral forelimb stepping was completely normalized. The extent of striatal denervation in the individual lesioned and treated animals was well correlated with the performance of the affected limb in the stepping test. These results show that intrastriatal glial cell line-derived neurotrophic factor can stimulate substantial axonal sprouting and reinnervation of the partially deafferated striatum to a degree sufficient to reverse the lesion-induced deficit in spontaneous motoric behaviour, indicating that a direct action of glial cell line-derived neurotrophic factor on spared dopaminergic afferents in the striatum may be important for functional recovery in the rat Parkinson model.