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 modifie d to express recombinant nerve growth factor (NGF) support the surviva l and neuronal transdifferentiation of intrastriatal adrenal chromaffi n cell grafts at 2 weeks post-transplantation [15]. The present study was performed to determine whether these effects would be maintained a t longer limes post-transplantation and, if so, whether the co-grafts would reduce rotational behavior in the unilateral 6-hydroxydopamine-l esioned rat. In the present study, we have demonstrated that primary t ype 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 m odified astrocytes were also found to express recombinant NGF followin g intrastriatal transplantation, as indicated by a 23% increase in str iatal NGF content compared with controls, measured at 4 weeks post-tra nsplantation. When NGF-producing astrocytes and adrenal chromaffin cel ls were co-grafted into the dopamine-denervated striatum of the unilat eral 6-hydroxydopamine-lesioned rat, the chromaffin cells displayed ex tensive neurite outgrowth and a 5-12-fold increase in survival compare d to controls at 10 weeks post-grafting. These effects were paralleled by a 60% reduction of apomorphine-induced rotational behavior, sugges ting a partial normalization of striatal function. These results sugge st that genetically modified astrocytes promote the prolonged survival and function of adrenal chromaffin cell grafts in a rat model of Park inson's disease.