Implantation of bioactive growth factor-secreting rods enhances fetal dopaminergic graft survival, outgrowth density, and functional recovery in a rat model of Parkinson's disease.

One of the drawbacks with fetal ventral mesencephalic (VM) grafts in Parkinson's disease is the limited outgrowth into the host striatum. In order to enhance graft outgrowth, epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) were administered by implantation of bioactive rods to the lateral part of the striatum to support grafted fetal VM implanted to the medial portion of the striatum. The polymer-based bioactive rods allow for a local secretion of neurotrophic factors over a time period of approximately 2 weeks. Moreover, glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor-beta1 (TGFbeta1) were administered using the same technique. Concomitant administration of GDNF and TGFbeta1 was achieved by insertion of one GDNF and one TGFbeta1 rod. This was performed to investigate possible additive effects between GDNF and TGFbeta1. Rotational behavior, outgrowth from and nerve fiber density within the VM graft, and the number of TH-positive cells were studied. Functional compensation by reduction of rotational behavior was significantly enhanced in animals carrying bFGF and GDNF rods in comparison with animals carrying only VM graft. EGF and bFGF significantly increased the innervation density. Moreover, the nerve fiber density within the grafts was significantly enhanced by bFGF. Cell counts showed that a significantly higher number of TH-positive neurons was found in grafts treated with bFGF than that found in GDNF-treated grafts. An additive effect of TGFbeta1 and GDNF was not detectable. These results suggest that bioactive rods is a useful tool to deliver neurotrophic factors into the brain, and since bFGF was a potent factor concerning both functional, immunohistochemical and cell survival results, it might be of interest to use bFGF-secreting rods for enhancing the overall outcome of VM grafts into patients suffering from Parkinson's disease.

Törnqvist N ，Björklund L ，Almqvist P ，Wahlberg L ，Strömberg I ... -  《EXPERIMENTAL NEUROLOGY》

Dissociation between short-term increased graft survival and long-term functional improvements in Parkinsonian rats overexpressing glial cell line-derived neurotrophic factor.

Georgievska B ，Carlsson T ，Lacar B ，Winkler C ，Kirik D ... -  《EUROPEAN JOURNAL OF NEUROSCIENCE》

Continuous exposure to glial cell line-derived neurotrophic factor to mature dopaminergic transplants impairs the graft's ability to improve spontaneous motor behavior in parkinsonian rats.

Winkler C ，Georgievska B ，Carlsson T ，Lacar B ，Kirik D ... -  《NEUROSCIENCE》

Glial cell line-derived neurotrophic factor improves survival of dopaminergic neurons in transplants of fetal ventral mesencephalic tissue.

This study was designed to determine whether or not an exogenous source of glial cell line-derived neurotrophic factor (GDNF) could be delivered continuously into the denervated/transplanted striatum and stimulate the survival, growth, and function of fetal ventral mesencephalic tissue transplants. Adult male rats with unilateral 6-hydroxydopamine lesions received transplants of fetal ventral mesencephalic tissue into the denervated striatum. Immediately thereafter, osmotic pumps [Alzet 2002, 0.5 microliter/h] were attached to intracerebral cannula and either a citrate buffer alone [control] or r-methuGDNF [dissolved in sodium citrate buffer to a concentration of 0.45 microgram/microliter] was infused into a site approximately 1.0 mm lateral to the transplant for a 2-week period; one group of lesioned animals did not receive transplants but was infused with GDNF. The effect of GDNF on tyrosine hydroxylase-positive (TH+) fiber outgrowth from transplants was variable, and image analysis revealed no significant difference between the GDNF and citrate groups. In contrast, the mean number of TH+ cells bodies in transplants infused with GDNF [2,037 +/- 149, n = 8] vs citrate [663 +/- 160, n = 8] was statistically significant (P < 0.001); cell counts were made in every third brain section [35 micrometer]. Similarly, transplants infused with GDNF showed an over-compensatory effect to amphetamine-induced rotational behavior that was significantly lower than that observed in transplanted animals receiving citrate buffer infusions. Infusions of GDNF into the denervated striatum alone had no significant effect on amphetamine-induced rotational behavior or on TH fiber morphology in the lesioned striatum. Thus, a continuous infusion of GDNF can improve the survivability of dopaminergic neurons in transplants of fetal ventral mesencephalic tissue.

Yurek DM 《EXPERIMENTAL NEUROLOGY》

Effects of GDNF pretreatment on function and survival of transplanted fetal ventral mesencephalic cells in the 6-OHDA rat model of Parkinson's disease.

Andereggen L ，Meyer M ，Guzman R ，Ducray AD ，Widmer HR ... -  《-》