Implanted BDNF-producing fibroblasts prevent neurotoxin-induced serotonergic denervation in the rat striatum

Degeneration of serotonergic fibers in the rat striatum was produced by loc al administration of the serotonergic neurotoxin 5,7-dihydroxytryptamine (5 ,7-DHT) or the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium (MPP+), which is also toxic to serotonergic neurons. One week before neurotoxin adm inistration, fibroblasts engineered to express the human BDNF gene were gra fted into the mesencephalon, dorsal to the substantia nigra. Rats implanted with fibroblasts expressing the LacZ gene were used as controls, as well a s sham-operated animals (not injected with any neurotoxin). After a surviva l period of 1 week, the serotonergic innervation of the striatum was assess ed by measuring serotonin (5-HT) content and by immunohistochemical detecti on of 5-HT positive fibers. BDNF-producing cells prevented the striatal 5-H T loss induced by local administration of either 5,7-DHT or MPP+, as well a s the striatal dopamine (DA) loss induced by the latter neurotoxin. Graftin g of fibroblasts carrying the BDNF or the Lac-Z gene did not modify striata l 5-HT or DA content in sham-operated animals. In 5,7-DHT-lesioned rats, im planted or not with control Lac-Z fibroblasts, a striking reduction in the density of 5-HT immunoreactive fibers was observed. By contrast, the densit y of 5-HT fibers was similar in rats implanted with BDNF-producing fibrobla sts as compared to sham-operated controls. The protective effect of BDNF on the damage to serotonergic terminals induced by the two neurotoxins sugges ts the interest of this neurotrophin in the treatment of behavioral disorde rs associated to neurodegenerative diseases. (C) 2000 Elsevier Science B.V. All rights reserved.