Long-term survival of encapsulated GDNF secreting cells implanted within the striatum of parkinsonized rats

• Published in: International journal of pharmaceutics Vol. 343; no. 1; pp. 69 - 78
• Main Authors: Grandoso, Laura, Ponce, Sara, Manuel, Ivan, Arrúe, Aurora, Ruiz-Ortega, Jose A., Ulibarri, Isabel, Orive, Gorka, Hernández, Rosa M., Rodríguez, Alicia, Rodríguez-Puertas, Rafael, Zumárraga, Mercedes, Linazasoro, Gurutz, Pedraz, Jose Luis, Ugedo, Luisa
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.10.2007; Elsevier
• Subjects: 3,4-Dihydroxyphenylacetic Acid - metabolism; 6-OHDA lesion; Animals; Behavior, Animal - drug effects; Biological and medical sciences; Cell Line; Cell Survival; Corpus Striatum - drug effects; Corpus Striatum - metabolism; Dopamine - metabolism; Drug Compounding; Drug Delivery Systems; Fibroblasts - cytology; Fibroblasts - metabolism; General pharmacology; Glial cell line-derived neurotrophic factor (GDNF); Glial Cell Line-Derived Neurotrophic Factor - administration & dosage; Glial Cell Line-Derived Neurotrophic Factor - pharmacokinetics; Glial Cell Line-Derived Neurotrophic Factor - therapeutic use; Homovanillic Acid - metabolism; Immunohistochemistry; Levodopa - metabolism; Male; Medical sciences; Microencapsulation; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - pharmacokinetics; Neuroprotective Agents - therapeutic use; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson Disease - physiopathology; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Rats; Rats, Sprague-Dawley; Rotational behavior; Immunohistochemistry; Microencapsulation; Rotational behavior; 6-OHDA lesion; Glial cell line-derived neurotrophic factor (GDNF); Encapsulation; Pharmaceutical technology; Implant; Rat; Rodentia; In vitro; Long term; Survival; Vertebrata; Mammalia; Animal; Glial cell line derived neurotrophic factor; Behavior; Lesion
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2007.05.027

Several findings suggest that glial cell line-derived neurotrophic factor (GDNF) may be a useful tool to treat parkinsonism by acting as a neuroprotective and neurotrophic factor for dopaminergic neurotransmission systems. In the present study, we implanted alginate-poly-L-lysine-alginate microcapsules containing immobilized Fischer rat 3T3 fibroblasts transfected to produce GDNF in vitro into the striatum of 6-hydroxydopamine (6-OHDA) lesioned rats. Microencapsulated GDNF secreting cells were stable for at least 3 weeks in vitro. Intrastriatal implantation of microencapsulated GDNF secreting cells into 6-OHDA lesioned rats resulted in a decrease in apomorphine-induced rotations by 84%, 64%, 84%, 60% and 52% (2, 5, 8, 16 and 24 weeks, respectively) with respect to the value before implantation and with respect to the value obtained from the empty microcapsule implanted-group at each time point. Six months after transplantation, immunohistochemical detection of GDNF revealed strong immunoreactivity in the striatal tissue surrounding the microcapsules in the absence of tissue damage due to microcapsule implantation. No changes in the levels of dopamine and its metabolites or of tyrosine hydroxylase immunoreactivity were detected in the striatum. In summary, the implantation of microencapsulated GDNF secreting cells allows the delivery of this molecule into the rat striatum for at least 6 months and results in substantial behavioral improvement.