M. Johansson et al., EFFECTS OF GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR ON DEVELOPING AND MATURE VENTRAL MESENCEPHALIC GRAFTS IN OCULO, Experimental neurology, 134(1), 1995, pp. 25-34
The search for trophic factors that can support injured dopaminergic n
eurons and can enhance dopaminergic graft survival and outgrowth for t
herapeutic uses in Parkinson's disease has lately focused on members o
f the transforming growth factor (TGF) beta superfamily. In this paper
we have studied the effects of a member of the TGB beta family, glial
cell line-derived neurotrophic factor (GDNF), on immature and mature
ventral mesencephalic tissue grafted to the anterior chamber of the ey
e. The results confirm that GDNF increases survival of TH-positive neu
rons and enhances TH-immunoreactive nerve fiber formation when the gra
fts are treated during their development. The distribution of nerve te
rminals is densest within the area of TH-immunoreactive neurons and at
the surface of the grafts. However, there is no change in the number
of calcium-binding protein (CaBP)-positive neurons, suggesting that th
e subpopulation of TH-positive neurons that is increased are the CaBP-
negative neurons of the ventral tier of pars compacta. Terminals from
those neurons form the striatal patches during normal development. Whe
n the grafts are treated with GDNF after maturation, no change in TH-p
ositive cell survival is seen but an increase of nerve terminals is st
ill found within the cell dense area of the graft. Potassium-evoked do
pamine release, measured using irt vivo chronoamperometry, revealed si
gnificantly increased extracellular overflow in transplants treated wi
th GDNF during development. The dopamine uptake blocker nomifensine si
gnificantly increased the time for clearance of the released dopamine.
These data suggest that GDNF treatment of immature grafts enhances su
rvival of TH-positive neurons, which would have innervated the striata
l patches, and also increases TH-immunoreactive nerve fiber formation
and dopamine release. Furthermore, GDNF treatment of mature grafts als
o increases dopamine fiber formation within the TH-positive neuronal a
rea, indicating that adult dopaminergic neurons are also responsive to
this agent. (C) 1995 Academic Press, Inc.