NERVE GROWTH-FACTOR RELEASED BY TRANSGENIC ASTROCYTES ENHANCES THE FUNCTION OF ADRENAL CHROMAFFIN CELL GRAFTS IN A RAT MODEL OF PARKINSONS-DISEASE

Previous studies have demonstrated that astrocytes genetically modified to express recombinant nerve growth factor (NGF) support the survival and neuronal transdifferentiation of intrastriatal adrenal chromaffin cell grafts at 2 weeks post-transplantation [15]. The present study was performed to determine whether these effects would be maintained at longer limes post-transplantation and, if so, whether the co-grafts would reduce rotational behavior in the unilateral 6-hydroxydopamine-lesioned rat. In the present study, we have demonstrated that primary type I rat astrocytes infected with a replication-defective retrovirus conferring expression of a mouse beta-NGF cDNA sequence secrete NGF at a rate that is approximately 40-fold higher than that of controls (i.e., 8.0 vs. 0.2 pg NGF/h/10(5) cells, respectively). The genetically modified astrocytes were also found to express recombinant NGF following intrastriatal transplantation, as indicated by a 23% increase in striatal NGF content compared with controls, measured at 4 weeks post-transplantation. When NGF-producing astrocytes and adrenal chromaffin cells were co-grafted into the dopamine-denervated striatum of the unilateral 6-hydroxydopamine-lesioned rat, the chromaffin cells displayed extensive neurite outgrowth and a 5-12-fold increase in survival compared to controls at 10 weeks post-grafting. These effects were paralleled by a 60% reduction of apomorphine-induced rotational behavior, suggesting a partial normalization of striatal function. These results suggest that genetically modified astrocytes promote the prolonged survival and function of adrenal chromaffin cell grafts in a rat model of Parkinson's disease.