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 semipermeable ultrafiltration membranes and implanted in the striatum, have some potential efficacy for the treatment of age- and 6-OHD-induced sensorimotor impairments (22, 70, 71, 74). The objectives of this study were 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 their ability to survive and produce catecholamines in vivo in a dopamine-depleted striatum, and (3) determine if BHK-GDNF, PC12, or PC12A cells reduce parkinsonian symptoms in a rodent model of Parkinson's disease. Capsules with BHK-GDNF or PC12 cells contained viable cells after 90 days in vivo, with little evidence of host tissue damage/gliosis. In rats with tyrosine hydroxylase (TH)-positive fibers remaining in the lesioned striatum, there was TH-positive fiber ingrowth into the membranes of the BHK-GDNF capsules. PC12-containing capsules had higher basal release of both dopamine and L-DOPA after 90 days in vivo than before implantation, while basal release of both dopamine and L-DOPA decreased in the PC12A-containing capsules. Both encapsulated PC12 and PC12A cells, but not encapsulated BHK-GDNF cells, decreased apomorphine-induced rotations. Parkinsonian symptoms (akinesia, freezing/bracing, sensorimotor neglect) related to the extent of dopamine depletion were evident even in rats with dopamine depletions of only 25%. Evidence that encapsulated cells may attenuate these parkinsonian symptoms was not detected but most of the rats were more severely depleted of dopamine than Parkinson's patients (less than 2% dopamine remaining in the entire striatum), and these tests were not sensitive to differences between rats with less than 10% dopamine remaining. These results suggest that cell encapsulation technology can safely provide site-specific delivery of dopaminergic agonists or growth factors within the CNS, without requiring suppression of the immune system, and without using fetal tissue. Of the three types of encapsulated cells examined in the present study, PC12 cells seem to offer the most therapeutic potential in rats with severe dopamine depletions.
Lindner
M D
MD
Cyto Therapeutics, Inc., Providence, Rhode Island 02906, USA.
Winn
S R
SR
Baetge
E E
EE
Hammang
J P
JP
Gentile
F T
FT
Doherty
E
E
McDermott
P E
PE
Frydel
B
B
Ullman
M D
MD
Schallert
T
T
D000818:Animals; D001483:Base Sequence; D001522:Behavior, Animal; D002214:Capsules; D002460:Cell Line; D003001:Cloning, Molecular; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000172:deficiency*; D004343:Drug Implants; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007668:Kidney; D007980:Levodopa / Q000378:metabolism*; D008297:Male; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000008:administration & dosage* / Q000235:genetics; D016627:Oxidopamine / Q000494:pharmacology; D016716:PC12 Cells / Q000378:metabolism*; D010300:Parkinson Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016133:Polymerase Chain Reaction; D051381:Rats; D017207:Rats, Sprague-Dawley; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D002214:Capsules; D004343:Drug Implants; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D007980:Levodopa; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine