GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR IMPROVES SURVIVAL OF VENTRAL MESENCEPHALIC GRAFTS TO THE 6-HYDROXYDOPAMINE LESIONED STRIATUM

One approach to replace lost dopaminergic neurons in Parkinson's disea se is to transplant fetal mesencephalic tissue into the striatum. In a n attempt to expand the developmental window useful for grafting of me sencephalic tissue and increase the fiber outgrowth from grafted dopam inergic neurons, we have pretreated fetal mesencephalic tissue with th e dopaminotrophic factor glial cell line-derived neurotrophic factor ( GDNF). Mesencephalic tissue pieces from embryonic day 18-19 Fischer 34 4 rats were preincubated for 20 min with GDNF (1 mu g/mu l) or vehicle . Two tissue pieces were then transplanted into the striatum of rats t hat had been unilaterally lesioned by medial forebrain bundle injectio ns of 6-hydroxydopamine, The animals were tested for apomorphine-induc ed rotations prior to intracranial grafting. Host rats received intras triatal injections of 10 mu g GDNF or control solution at 10 days and 4 weeks postgrafting. The animals were tested in the rotometer twice m onthly following transplantation. Despite the fact that these transpla nts were from a suboptimal donor stage, the rotations were significant ly decreased in both transplanted groups. Immunohistochemical evaluati on of the host brains revealed that the overall size of transplanted m esencephalic tissue was significantly increased in the GDNF-treated an imals, and that the average size of transplanted tyrosine hydroxylase (TH)-positive neurons was also increased. Furthermore, we found that t he innervation density of surrounding host striatal tissue was signifi cantly increased in the GDNF-treated group, as compared with controls. Taken together, these results suggest that treatment of intrastriatal ventral mesencephalon grafts with GDNF can optimize the conditions fo r intracranial grafting and thus improve the chances for functional re covery following the intrastriatal grafting procedure.