Long-term glial cell line-derived neurotrophic factor overexpression in the intact nigrostriatal system in rats leads to a decrease of dopamine and increase of tetrahydrobiopterin production

Autor: Sajadi, A., Bauer, M., Thony, B., Aebischer, P.
Předmět:
Tyrosine 3-Monooxygenase/metabolism
Corpus Striatum/drug effects/ metabolism/pathology/physiopathology
Genetic Vectors
Dose-Response Relationship
Membrane Transport Proteins/metabolism
Vesicular Biogenic Amine Transport Proteins
Animals
Glial Cell Line-Derived Neurotrophic Factor
Parkinson Disease/drug therapy/ metabolism/pathology
Presynaptic Terminals/drug effects/metabolism
urogenital system
Animal
Gene Expression Regulation/physiology
Lentivirus/genetics
Gene Transfer Techniques
Membrane Glycoproteins/metabolism
Nerve Growth Factors/ biosynthesis/genetics
Down-Regulation/genetics
Biopterin/ analogs & derivatives/biosynthesis/ metabolism
Rats
Neural Pathways/metabolism/physiopathology
nervous system
Substantia Nigra/drug effects/ metabolism/pathology
Disease Models
GTP Cyclohydrolase/metabolism
Female
Dopamine/ metabolism
Sprague-Dawley
Drug
Popis: Parkinson's disease (PD) is characterized by the progressive degeneration of the nigrostriatal dopaminergic system. Brain delivery of glial cell line-derived neurotrophic factor (GDNF) has been shown to protect and restore the dopaminergic pathway in various animal models of PD. However, GDNF overexpression in the dopaminergic pathway leads to a time-dependent down-regulation of tyrosine hydroxylase (TH), a key enzyme in dopamine synthesis. In order to elucidate GDNF-mediated biochemical effects on dopaminergic neurons, we overexpressed GDNF in the intact rat striatum using a lentiviral vector-mediated gene transfer technique. Long-term GDNF overexpression led to increased GTP cyclohydrolase I (GTPCH I) activity and tetrahydrobiopterin (BH4) levels. Further, we observed a down-regulation of TH enzyme activity in morphologically intact striatal dopaminergic nerve terminals, as well as a significant decrease of dopamine levels in striatal tissue samples. These results indicate that long-term GDNF delivery is a major factor affecting dopamine biosynthesis via a direct or indirect modulation of TH and GTPCH I and further underscore the importance of assessing both GDNF dose and delivery duration prior to clinical application in order to circumvent potentially adverse pharmacological effects on the biosynthesis of dopamine.
Databáze: OpenAIRE
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