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 Parkin son'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 t o the lateral part of the striatum to support grafted fetal VIM implanted t o the medial portion of the striatum. The polymer-based bioactive rods allo w for a local secretion of neurotrophic factors over a time period of appro ximately 2 weeks. Moreover, glial cell line-derived neurotrophic factor (GD NF) and transforming growth factor-beta 1 (TGF beta 1) were administered us ing the same technique. Concomitant administration of GDNF and TGF beta 1 w as achieved by insertion of one GDNF and one TGF beta 1 rod. This was perfo rmed to investigate possible additive effects between GDNF and TGF beta 1. Rotational behavior, outgrowth from and nerve fiber density within the VM g raft, and the number of TH-positive cells were studied. Functional compensa tion by reduction of rotational behavior was significantly enhanced in anim als carrying bFGF and GDNF rods in comparison with animals carrying only VM graft. EGF and bFGF significantly increased the innervation density. Moreo ver, the nerve fiber density within the grafts was significantly enhanced b y bFGF. Cell counts showed that a significantly higher number of TH-positiv e neurons was found in grafts treated with bFGF than that found in GDNF-tre ated grafts. An. additive effect of TGF beta 1 and GDNF was not detectable. These results suggest that bioactive rods is a useful tool to deliver neur otrophic factors into the brain, and since bFGF was a potent factor concern ing both functional, immunohistochemical and cell survival results, it migh t be of interest to use bFGF-secreting rods for enhancing the overall outco me of VM grafts into patients suffering from Parkinson's disease. (C) 2000 Academic Press.