GDNF triggers fiber outgrowth of fetal ventral mesencephalic grafts from nigra to striatum in 6-OHDA-lesioned rats

Previous reports have indicated that grafting of fetal ventral mesencephalic tissue to the nigra region of animals unilaterally lesioned with 6-hydroxydopamine (6-OHDA), in conjunction with kainate injection between the nigra and striatum, restores nigrostriatal tyrosine hydroxylase immunoreactivity. Glial-cell-line-derived neurotrophic factor (GDNF), a potent trophic factor for dopaminergic neurons, has been found to be upregulated by kainate. We have investigated the bridging effect of GDNF injection on intra-nigral transplants. Adult Sprague-Dawley rats were anesthetized and unilaterally injected with 6-OHDA into the medial forebrain bundle. The completeness of lesions was tested by measuring methamphetamine-induced rotations. Some 1-2 months after 6-OHDA administration, fetal ventral mesencephalic tissues were grafted into the lesioned nigral area followed by injection of 100 mu g GDNF, along a tract from the nigra to striatum. Animals receiving transplantation and GDNF injection showed a significant decrease in rotation 1-3 months after grafting. Immunocytochemical studies indicated that tyrosine-hydroxylase-positive neurons and fibers were present in the nigra and striatum, respectively, after grafting. No effects of similarly injected brain-derived neurotrophic factor were seen. These results indicate that fetal nigral transplantation and GDNF injection restore the nigrostriatal dopaminergic pathway in Parkinsonian animals and support the hypothesis of trophic activity of GDNF on midbrain dopaminergic neurons.