IMPLANTATION OF ENCAPSULATED CATECHOLAMINE AND GDNF-PRODUCING CELLS IN RATS WITH UNILATERAL DOPAMINE DEPLETIONS AND PARKINSONIAN SYMPTOMS

Studies in rodents suggest that PC12 cells, encapsulated in semipermea ble ultrafiltration membranes and implanted in the striatum, have some potential efficacy for the treatment of age- and 6-OHDA-induced senso rimotor impairments (22, 70, 71, 74). The objectives of this study wer e to: (1) determine if baby hamster kidney cells engineered to secrete glial cell line-derived neurotrophic factor (BHK-GDNF) would survive encapsulation and implantation in a dopamine-depleted rodent striatum, (2) compare polymer-encapsulated PC12 and PC12A cells in terms of the ir ability to survive and produce catecholamines in vivo in a dopamine -depleted striatum, and (3) determine if BHK-GDNF, PC12, or PC 12A cel ls reduce parkinsonian symptoms in a rodent model of Parkinson's disea se. Capsules with BHK-GDNF or PC12 cells contained viable cells after 90 days in vivo, with little evidence of host tissue damage/gliosis. I n rats with tyrosine hydroxylase (TH)-positive fibers remaining in the lesioned striatum, there was TH-positive fiber ingrowth into the memb ranes of the BHK-GDNF capsules. PC12-containing capsules had higher ba sal release of both dopamine and L-DOPA after 90 days in vivo than bef ore implantation, while basal release of both dopamine and L-DOPA decr eased in the PC12A-containing capsules. Both encapsulated PC12 and PC1 2A cells, but not encapsulated BHK-GDNF cells, decreased apomorphine-i nduced rotations. Parkinsonian symptoms (akinesia, freezing/bracing, s ensorimotor neglect) related to the extent of dopamine depletion were evident even in rats with dopamine depletions of only 25%. Evidence th at encapsulated cells may attenuate these parkinsonian symptoms was no t detected but most of the rats were more severely depleted of dopamin e than Parkinson's patients (less than 2% dopamine remaining in the en tire striatum), and these tests were not sensitive to differences betw een rats with less than 10% dopamine remaining. These results suggest that cell encapsulation technology can safely provide site-specific de livery of dopaminergic agonists or growth factors within the CNS, with out requiring suppression of the immune system, and without using feta l tissue. Of the three types of encapsulated cells examined in the pre sent study, PC12 cells seem to offer the most therapeutic potential in rats with severe dopamine depletions. (C) 1995 Academic Press, Inc.