Therapeutic effects of astrocytes expressing both tyrosine hydroxylase and brain-derived neurotrophic factor on a rat model of Parkinson's disease.
Tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF), expressed in normal astrocytes, were used in combination for the treatment of Parkinson's disease (PD) symptoms in a rat model. Normal neonatal rat astrocytes were co-transfected with a vector expressing BDNF (AAVBDNF) and a retroviral vector expressing TH (termed TH-BDNF-DA(+) cells), and then implanted into the striatum of PD rats induced by 6-hydroxydopamine. TH-BDNF-DA(+) cells compensated for a severe insufficiency of endogenous dopaminergic neurons in the PD rats, resulting in a significant improvement of PD symptoms. The decrease in the rotational rate of PD rats implanted with TH-BDNF-DA(+) cells was more marked than that in PD rats implanted with normal astrocytes expressing either TH or BDNF alone (termed TH(+) and BDNF(+) cells, P<0.01 and 0.001, respectively), and suggested a synergistic effect between TH and BDNF. In contrast, the rotational rate was not altered from the baseline in PD rats without treatment or implanted with parental rat astrocytes alone (P>0.05). BDNF protected the dopaminergic neurons from apoptosis induced by 6-hydroxydopamine, and significantly increased the long-term survival of TH-positive cells in the striatum. Our data indicate that the combined use of TH and BDNF has a synergistic therapeutic effect, and is more efficient for the treatment of PD than a single gene therapy using either TH or BDNF alone.
Wang
Z H
ZH
Department of Neurology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
Ji
Y
Y
Shan
W
W
Zeng
B
B
Raksadawan
N
N
Pastores
G M
GM
Wisniewski
T
T
Kolodny
E H
EH
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001253:Astrocytes / Q000378:metabolism*; D001522:Behavior, Animal; D015153:Blotting, Western; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018929:Cell Culture Techniques; D002470:Cell Survival / Q000235:genetics; D003342:Corpus Striatum / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D007150:Immunohistochemistry; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000378:metabolism / Q000628:therapy*; D012333:RNA, Messenger; D051381:Rats; D012190:Retroviridae; D013378:Substantia Nigra / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine