Influence of BDNF on the expression of the dopaminergic phenotype of tissue used for brain transplants

Abstract

Brain-derived neurotrophic factor (BDNF) has previously been shown by this laboratory among others to promote survival and differentiation of central dopaminergic neurons and to stimulate expression of the dopaminergic phenotype in fetal cerebrocortex in vitro. We have examined the effect of BDNF antibody on nigral dopaminergic neurons in vivo and in vitro. It reduced the survival of rat fetal dopaminergic neurons in culture (up to 40% died). The BDNF antibody also caused ipsilateral rotation after a single in vivo intranigral injection in the adult rats. Pre-treatment of fetal nigral neurons with BDNF improved the performance of dopaminergic cells in fetal nigral transplants based on surviving TH + cells numbers. Thus, parkinsonian rats receiving fetal nigral cells treated with BDNF showed a significantly greater reduction of turning over the 3 weeks following transplantation, compared with the rats receiving untreated nigral transplants. However, the average number of tyrosine hydroxylase (TH)-positive neurons in the grafts of rats receiving fetal nigral cells treated with BDNF was 211±35 which was only about 20% of the cell number (1012±223, mean±S.E.M.) found in those receiving untreated nigral transplants. These results suggest that pretreatment of nigral dopaminergic neurons with BDNF may improve their functional performance, but not their survival in transplants. The ability of artificially induced cerebrocortical `dopaminergic' cells to ameliorate behavioral asymmetry of Parkinsonian rats was assessed. A proportion (1.0% maximum) of the TH + neurons in these transplants survived in the host brain and were likely to be responsible for the prominent reduction in rotation scores observed to occur 6 weeks after implantation. Thus, the combined treatment of fetal cerebral cortex with BDNF and dopamine created long-lived TH-expressing neuronal populations which were very effective in alleviating the rat parkinsonian model, and thus may be suitable for use in transplantation in treating human Parkinson's disease.