Reversible neurochemical changes mediated by delayed intrastriatal glial cell line-derived neurotrophic factor gene delivery in a partial Parkinson's disease rat model

• Published in: The journal of gene medicine Vol. 11; no. 10; pp. 899 - 912
• Main Authors: Yang, Xin, Mertens, Birgit, Lehtonen, Enni, Vercammen, Linda, Bockstael, Olivier, Chtarto, Abdelwahed, Levivier, Marc, Brotchi, Jacques, Michotte, Yvette, Baekelandt, Veerle, Sarre, Sophie, Tenenbaum, Liliane
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.10.2009; Wiley Periodicals Inc
• Subjects: 6-hydroxydopamine; adeno-associated viral vector; Adeno-associated virus; Adrenergic Agents - administration & dosage; Adrenergic Agents - adverse effects; Animals; Dependovirus - genetics; Dopamine - analysis; Dopamine - biosynthesis; Doxycycline - administration & dosage; Female; Gene Expression - drug effects; Gene therapy; Gene Transfer Techniques; Genetic Vectors - administration & dosage; Genetic Vectors - genetics; Genetic Vectors - metabolism; glial cell line-derived neurotrophic factor; Glial Cell Line-Derived Neurotrophic Factor - administration & dosage; Glial Cell Line-Derived Neurotrophic Factor - biosynthesis; Glial Cell Line-Derived Neurotrophic Factor - genetics; Humans; Motor Activity - drug effects; Oxidopamine - administration & dosage; Oxidopamine - adverse effects; Parkinson Disease, Secondary - chemically induced; Parkinson Disease, Secondary - metabolism; Parkinson Disease, Secondary - therapy; Parkinson's disease; phosphorylation; Rats; tetracycline-inducible; Time Factors; Tyrosine 3-Monooxygenase - analysis; Tyrosine 3-Monooxygenase - biosynthesis; tyrosine hydroxylase
• ISSN: 1099-498X; 1521-2254; 1521-2254
• DOI: 10.1002/jgm.1377

Background Efficient protection of dopaminergic neurons against a subsequent 6‐hydroxydopamine lesion by glial cell line‐derived neurotrophic factor (GDNF) gene delivery has been demonstrated. By contrast, the neurorestorative effects of GDNF administered several weeks after the toxin have been less characterized. In particular, whether these were permanent or dependent on the continuous presence of GDNF remains elusive. Methods A tetracycline‐inducible adeno‐associated virus (AAV)‐1 vector expressing human GDNF cDNA was administered unilaterally in the rat striatum 5 weeks after 6‐hydroxydopamine. Rats were treated with doxycycline (dox) or untreated from the day of vector injection until sacrifice (4 or 14 weeks). A sub‐group was dox‐treated for 7 weeks then untreated until 14 weeks. The motor behavior was assessed by amphetamine‐induced rotations and spontaneous forelimb asymmetry. The amounts of tyrosine hydroxylase (TH), serine‐40‐phosphorylated TH (S40‐TH) and aromatic amino acid decarboxylase (AADC) proteins were compared by western blotting and the dopamine levels quantified by high‐performance liquid chromatography. Results Dox‐dependent behavioral improvements were demonstrated 4 weeks post‐vector injection. At later time points, spontaneous partial recovery was observed in all rats, but no further improvement was found in dox‐treated animals. TH levels were significantly increased in dox‐treated rats at all time points. By contrast, striatal dopamine and S40‐TH were increased at 4 weeks, but not 14 weeks, and AADC remained unchanged. Dox withdrawal after 7 weeks, resulted in TH levels comparable to the controls at 14 weeks. Conclusions Delayed GDNF gene delivery only transiently improved dopaminergic function. Over the long term, TH was more abundant, but not functional, and the increase was lost when GDNF gene expression was switched off. Copyright © 2009 John Wiley & Sons, Ltd.