GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR IMPROVES INTRASTRIATAL GRAFT-SURVIVAL OF STORED DOPAMINERGIC CELLS

Glial cell line-derived neurotrophic factor, the newest member of the transforming growth factor-beta superfamily, has been shown to promote the survival and differentiation of dopaminergic neurons in the ventr al mesencephalon. Glial cell line-derived neurotrophic factor has been implicated in both the in vitro and in vivo recovery of mesencephalic dopaminergic cells challenged with the neurotoxins 1-methyl-4-phenylp yridinium and 6-hydroxydopamine. Previous studies have shown increased survival of intrastriatally transplanted dopaminergic cells when foll owed by infusion of neurotrophic factors such as basic fibroblast grow th factor, brain-derived neurotrophic factor and glial cell line-deriv ed neurotrophic factor. However, the effects of glial cell line-derive d neurotrophic factor co-administered with dopaminergic cells prior to implantation in the host striatum have not been studied. In the prese nt study, the hypothesis was that treating fetal ventral mesencephalic tissue containing the dopaminergic substantia nigra with glial cell l ine-derived neurotrophic factor, either during storage or at the time of transplantation, would enhance grafted dopaminergic cell survival a nd functional reinnervation of the host striatum in the unilaterally 6 -hydroxydopamine-lesioned rat. To test this hypothesis, two experiment s were performed. In the first experimental group (n=7), fetal ventral mesencephalons from embryonic day 14 rats were maintained in hibernat ion medium containing glial cell line-derived neurotrophic factor (1 m u g/ml) at 4 degrees C for six days prior to dissociation and stereota ctic implantation into the host striatum; the control group (n=5) rece ived tissue hibernated without glial cell line-derived neurotrophic fa ctor. The second experimental group (n=8) received fresh fetal ventral mesencephalic tissue treated with glial cell line-derived neurotrophi c factor (0.2 mu g/mu l) while the control group (n=5) received the fr esh graft with no glial cell line-derived neurotrophic factor. Transpl antation success was assessed by behavioural analysis (rotometry) and tyrosine hydroxylase immunohistochemistry. Cell counts of tyrosine hyd oxylase-stained sections revealed a statistically significant increase in tyrosine hydroxylase-positive neurons in grafts exposed to glial c ell line-derived neurotrophic factor during hibernation as compared to control grafts. In addition, there was a statistically significant en hancement of fibre density in the glial cell line-derived neurotrophic factor hibernation graft group as compared to the glial cell line-der ived neurotrophic factor fresh graft group. Behavioural analysis three weeks post-grafting exhibited a statistically significant decrease in amphetamine-induced rotations in animals transplanted with glial cell line-derived neurotrophic factor grafts as compared to control grafts . These findings suggest that storing dopaminergic cells in a glial ce ll line-derived neurotrophic factor-containing medium prior to transpl antation increases graft survival, graft derived fibre outgrowth, and behavioural recovery in the adult host. This observation has potential implications for enhancing the efficacy of neural transplantation in the treatment of Parkinson's disease. (C) 1997 IBRO. Published by Else vier Science Ltd.