INTRASTRIATAL IMPLANTATION OF FIBROBLASTS GENETICALLY-ENGINEERED TO PRODUCE BRAIN-DERIVED NEUROTROPHIC FACTOR PREVENTS DEGENERATION OF DOPAMINERGIC-NEURONS IN A RAT MODEL OF PARKINSONS-DISEASE

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of the dopaminergic neurons of the substantia n igra pars compacta (SNpc). Although various treatments are successfull y used to alleviate the symptoms of PD, none of them prevents or halts the neurodegenerative process of the disease. Brain-derived neurotrop hic factor (BDNF), a member of the neurotrophin family of proteins, su pports the survival and the differentiation of dopaminergic neurons. B DNF also prevents the death of dopaminergic neurons in vitro, which su ggests that it may be of possible use in the development of neuroprote ctive therapies for PD. To determine whether BDNF is neuroprotective f or SNpc dopaminergic neurons in the adult brain, we used a rat model o f PD in which degeneration of 60-70% of these neurons was induced by a n intrastriatal injection of 6-hydroxydopamine (6-OHDA). We report her e that intrastriatal grafts of fibroblasts genetically engineered to p roduce BDNF partially prevent the loss of nerve terminals and complete ly prevent the loss of cell bodies of the nigrostriatal dopaminergic p athway that is induced by the intrastriatal injection of 6-OHDA. In co ntrast, the implantation of control fibroblasts that did not produce B DNF failed to protect nerve terminals and cell bodies against 6-OHDA-i nduced damage. Our observation that grafts of BDNF-producing fibroblas ts protect against 6-OHDA-induced degeneration of SNpc dopaminergic ne urons in the adult rat brain opens new perspectives for treatments aim ed at the prevention of neurodegeneration in PD, using gene therapy an d neurotrophic factors such as BDNF.