Implantation of encapsulated catecholamine and GDNF-producing cells in rats with unilateral dopamine depletions and parkinsonian symptoms

Implantation of encapsulated catecholamine and GDNF-producing cells in rats with unilateral... 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-OHDA-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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Experimental Neurology Elsevier

Implantation of encapsulated catecholamine and GDNF-producing cells in rats with unilateral dopamine depletions and parkinsonian symptoms

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Publisher
Elsevier
Copyright
Copyright © 1995 Elsevier Ltd
ISSN
0014-4886
D.O.I.
10.1016/0014-4886(95)90059-4
Publisher site
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Abstract

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-OHDA-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.

Journal

Experimental NeurologyElsevier

Published: Mar 1, 1995

References

  • Properties of PC12 pheochromocytoma cells transplanted to the adult rat brain
    Freed, W.J.; Patel-Vaidya, U.; Geller, H.M.
  • Dopamine agonists in Parkinson's disease: A look at apomorphine
    Lees, A.J.
  • Evidence for Long-Term Survival and Function of Dopaminergic Grafts in Progressive Parkinsons Disease
    Lindvall, O.; Sawle, G.; Widner, H.; Rothwell, J.C.; Bjorklund, A.; Brooks, D.; Brundin, P.; Frackowiak, R.; Marsden, C.D.; Odin, P.; Rehncrona, S.
  • Transplantation of fetal dopamine neurons in Parkinson's disease: One-year clinical and neurophysiological observations in two patients with putaminal implants
    Lindvall, O.; Widner, H.; Rehncrona, S.; Brundin, P.; Odin, P.; Gustavii, B.; Frackowiak, R.; Leenders, K.L.; Sawle, G.; Rothwell, J.C.
  • Levodopa-induced dyskinesias in Parkinson's disease: Clinical and pharmacological classification
    Luquin, M.R.; Scipioni, O.; Vaamonde, J.; Gershanik, O.; Obeso, J.A.
  • Striatal dopamine deficiency in Parkinson's disease: Role of aging
    Scherman, D.; Desnos, C.; Darchen, F.; Pollak, P.; Javoy-Agid, F.; Agid, Y.
  • Chronic implants of chromaffin tissue into the dopamine-denervated striatum. Effects of NGF on graft survival, fiber growth and rotational behavior
    Stromberg, I.; Herrera-Marschitz, M.; Ungerstedt, U.; Ebendal, T.; Olson, L.

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