Reversible neurochemical changes mediated by delayed intrastriatal glial cell line-derived neurotrophic factor gene delivery in a partial Parkinson's disease rat model.
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.
Yang
Xin
X
Laboratory of Experimental Neurosurgery, Université Libre de Bruxelles, Brussels, Belgium.
Mertens
Birgit
B
Lehtonen
Enni
E
Vercammen
Linda
L
Bockstael
Olivier
O
Chtarto
Abdelwahed
A
Levivier
Marc
M
Brotchi
Jacques
J
Michotte
Yvette
Y
Baekelandt
Veerle
V
Sarre
Sophie
S
Tenenbaum
Liliane
L
D018663:Adrenergic Agents / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004298:Dopamine / Q000032:analysis / Q000096:biosynthesis; D004318:Doxycycline / Q000008:administration & dosage; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D009043:Motor Activity / Q000187:drug effects; D016627:Oxidopamine / Q000008:administration & dosage / Q000009:adverse effects; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism* / Q000628:therapy*; D051381:Rats; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis / Q000096:biosynthesis
D018663:Adrenergic Agents; C495039:GDNF protein, human; D051100:Glial Cell Line-Derived Neurotrophic Factor; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004318:Doxycycline; D004298:Dopamine