ALLEVIATION OF BEHAVIORAL DEFICITS IN AGED RODENTS FOLLOWING IMPLANTATION OF ENCAPSULATED GDNF-PRODUCING FIBROBLASTS

The present study examined the effects of encapsulated cells which wer e genetically modified to secrete human glial-derived neurotrophic fac tor (hGDNF) on the motor deficits in aged rodents. Prior to implantati on, animals were tested on a battery of motor tasks. Spontaneous locom otion and motor coordination was evaluated in young (5 month) and aged (20 month) rats. Aged animals tested for spontaneous locomotor activi ty were found to be hypoactive relative to young animals. Compared to the young animals the aged animals also: (1) were impaired on a bar pr essing task, (2) were unable to descend a wooden pole covered with wir e mesh in a coordinated manner, (3) fell more rapidly from a rotating rod and (4) were unable to maintain their balance on a series of woode n beams of varying widths. Following baseline testing, aged animals re ceived either no implant, encapsulated baby hamster kidney fibroblast cells that were modified to produce hGDNF (BHK-hGDNF) or encapsulated BHK cells which were not modified to produce hGDNF (BHK-Control) impla nted bilaterally into the striatum. Following surgery, a significant i ncrease in locomotor activity and bar pressing was observed in those a ged animals receiving BHK-hGDNF implants. Bar pressing in aged animals receiving BHK-Control cells was improved to a lesser extent and reach ed the level of performance seen in young rats. No recovery was observ ed in the animals receiving BHK-Control cell-loaded capsules on any of the other motor tasks. Histological analysis revealed that implants o f hGDNF-producing cells produced a marked increase in the density of t yrosine hydroxylase staining in the striatum adjacent to the implant s ite. This increased staining was not seen in animals receiving BHK-Con trol cells. Histological analysis also revealed the presence of viable BHK-hGDNF cells within the capsules that continued to produce hGDNF a s measured by ELISA. These results indicate that polymer-encapsulated hGDNF-secreting cells survive following implantation into aged rats an d may be useful for treating some of the behavioral consequences of ag ing or disorders characterized by dopaminergic hypofunction.