Adenovirus-mediated transduction with human glial cell line-derived neurotrophic factor gene prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopamine depletion in striatum of mouse brain.
As a novel trial of neuroprotective therapy of neurodegenerative diseases, we have constructed a recombinant adenovirus vector (rAdv) bearing a neurotrophic factor gene to deliver the factor to rescue neurons in vivo. In the present study, human glial cell line-derived neurotrophic factor (hGDNF) was chosen to examine the applicability of our strategy to a mouse model of Parkinson's disease. During the construction of the rAdv, we found that the strong constitutive hGDNF expression unit somehow inhibited the appearance of the rAdv. Therefore we adopted a self-contained tetracycline-regulated expression system to acquire an rAdv expressing hGDNF. By analyzing the condition medium of SH-SY5Y cells infected with our constructed virus vector, we confirmed that biologically active GDNF was successfully expressed in vitro. For an animal study, we delivered this virus vector directly to the C57 black mouse brain and then exposed the animal to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to injure the nigrostriatal dopaminergic neurons. One week after the MPTP exposure, the neuroprotective effect of the virus vector was estimated by measurement of the dopamine content in the striatum of the mouse brain. The mice that had received our constructed virus had significantly higher dopamine levels in their striatum, demonstrating that our rAdv expressing hGDNF has therapeutic potential to protect the nigrostriatal dopaminergic neurons in vivo.
Kojima
H
H
Gifu International Institute of Biotechnology, Yagi Memorial Park, Mitake, Gifu, 505-01, Japan.
Abiru
Y
Y
Sakajiri
K
K
Watabe
K
K
Ohishi
N
N
Takamori
M
M
Hatanaka
H
H
Yagi
K
K
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D000256:Adenoviridae; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D004298:Dopamine / Q000235:genetics / Q000378:metabolism*; D015259:Dopamine Agents / Q000494:pharmacology*; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D008297:Male; D051379:Mice; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000008:administration & dosage* / Q000235:genetics; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000628:therapy
D015259:Dopamine Agents; C495039:GDNF protein, human; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D004298:Dopamine