A NOVEL IMMUNOPHILIN LIGAND - DISTINCT BRANCHING EFFECTS ON DOPAMINERGIC-NEURONS IN CULTURE AND NEUROTROPHIC ACTIONS AFTER ORAL-ADMINISTRATION IN AN ANIMAL-MODEL OF PARKINSONS-DISEASE

Protection or regeneration of the dopaminergic (DA) system would be of significant therapeutic value for Parkinson's disease. Immunophilin l igands, such as FK506, can produce neurotrophic effects in vitro and i n vivo, but their immunosuppressive effects make them unsuitable for n eurological application. This study demonstrates that a novel, nonimmu nosuppressive immunophilin ligand (V-10,367) increased the number of n eurites extended by tyrosine hydroxylase positive (TH+) DA neurons in embryonic day 14 primary DA neuronal cultures. In contrast, the immuno suppressive immunophilin ligand FK506 increased the length of TH+ neur ites. After oral administration in MPTP-treated mice, V-10,367 complet ely protected against MPTP-induced loss of striatal TH+ axonal density , while FK506 did not. These experiments demonstrate that nonimmunosup pressive immunophilin ligands specifically increase neurite branching in primary DA neuronal cultures and possess neurotrophic actions in vi vo with potential application to neurodegenerative disease. (C) 1998 A cademic Press.