INTRASTRIATAL IMPLANTS OF POLYMER ENCAPSULATED CELLS GENETICALLY-MODIFIED TO SECRETE HUMAN NERVE GROWTH-FACTOR - TROPHIC EFFECTS UPON CHOLINERGIC AND NONCHOLINERGIC STRIATAL NEURONS

Nerve growth factor selectively prevents the degeneration of cholinerg ic neurons following intrastriatal infusion but rescues both cholinerg ic and noncholinergic striatal neurons if the nerve growth factor is s ecreted from grafts of genetically modified fibroblasts. The present s tudy evaluated whether grafted fibroblasts genetically modified to sec rete human nerve growth factor could provide trophic influences upon i ntact cholinergic and noncholinergic striatal neurons. Unilateral stri atal grafts of polymer-encapsulated cells genetically modified to secr ete human nerve growth factor induced hypertrophy and significantly in creased the optical density of choline acetyltransferase-immunoreactiv e striatal neurons one, two, and four weeks post-transplantation relat ive to rats receiving identical grafts missing only the human nerve gr owth Factor construct. Nerve growth factor secreting grafts also induc ed a hypertrophy of noncholinergic neuropeptide Y-immunoreactive stria tal neurons one, two, and four weeks post-transplantation. Glutamic ac id decarboxylase-immunoreactive neurons were unaffected by the human n erve growth factor secreting grafts. The effects upon choline acetyltr ansferase-immunoreactive and neuropeptide Y-immunoreactive striatal ne urons dissipated following retrieval of the implants. Immunocytochemis try for nerve growth factor revealed intense graft-derived immunoreact ivity for up to 1000 mu m from the capsule extending along the dorsove ntral axis of the striatum. Nerve growth factor-immunoreactivity was a lso observed within a subpopulation of striatal neurons and may repres ent nerve growth Factor consumer neurons which retrogradely transporte d graft-derived nerve growth factor. When explanted, grafts produced 2 -4 ng human nerve growth factor/24 h over the time course of this stud y indicating that this level of continuous human nerve growth factor s ecretion was sufficient to mediate the effects presently observed.