CELL-MEDIATED DELIVERY OF BRAIN-DERIVED NEUROTROPHIC FACTOR ENHANCES DOPAMINE LEVELS IN AN MPP-NIGRA DEGENERATION( RAT MODEL OF SUBSTANTIA)

Brain-derived neurotrophic factor (BDNF) promotes the survival of feta l mesencephalic dopaminergic cells and protects dopaminergic neurons a gainst the toxicity of MPP+ in vitro, Supranigral implantation of fibr oblasts genetically engineered to secrete BDNF attenuates the loss of substantia nigra pars compacta (SNc) dopaminergic neurons associated w ith striatal infusion of MPP+ in the adult rat, Using this MPP+ rat mo del of nigral degeneration, we evaluated the neurochemical effects of supranigral, cell-mediated delivery of BDNF on substantia nigra (SN) d opamine (DA) content and turnover, Genetically engineered BDNF-secreti ng fibroblasts (similar to 12 ng BDNF/24 h) were implanted dorsal to t he SN 7 days prior to striatal MPP+ administration, The present result s demonstrate that BDNF-secreting fibroblasts, as compared to control fibroblasts, enhance SN DA levels ipsilateral as well as contralateral to the graft without altering DA turnover. This augmentation of DA le vels suggests that local neurotrophic factor delivery by genetically e ngineered cells may provide a therapeutic strategy for preventing neur onal death or enhancing neuronal function in neurodegenerative disease s characterized by dopaminergic neuronal dysfunction, such as Parkinso n's disease.