Antiparkinsonian trophic action of glial cell line-derived neurotrophic factor and transforming growth factor β1 is enhanced after co-infusion in rats

The objective was to analyze functional effects of the combination of GDNF and TGF-beta 1 in the retrograde model of Parkinsonism in rats, based on the intrastriatal infusion of 6-hydroxydopamine, which leads to protracted and progressive cell death in the substantia nigra. Hemiparkinsonian rats were implanted with osmotic minipumps 2 months after striatal lesion, pumps delivering GDNF alone (10 ng/day), TGF-beta 1 alone (2 ng/day), or a GDNF and TGF-beta 1 combination. The findings confirmed that GDNF alone has potent dopaminotrophic effects but they also revealed, for the first time, that GDNF and TGF-beta 1 co-infusion led to stronger trophic effects relative to the infusion of GDNF alone. TGF-beta 1 allowed further reducing dopamine receptor hypersensitivity, and potentiated GDNF-mediated effects. This cooperation could be accounted for by the recruitment of GFR alpha 1 on striatal membranes, and by enhanced expression and activation of TH through augmented pSer31TH and pSer40TH. Co-infusion induced striatal sprouting, as revealed by augmentation of p21-Arc, stathmin, and synaptophysin, and led to a reliable recovery of phenotypic expression of TH in surviving nigral neurons. Functional recovery and improvement of TH signal in the nigrostriatal system were long-lasting and sustained, remaining after cessation of trophic infusion. (C) 2010 Elsevier Inc. All rights reserved.