title: Therapeutic effects of astrocytes expressing both tyrosine hydroxylase and brain-derived neurotrophic factor on a rat model of Parkinson's disease.
abstract: 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.
authors.affiliation: Department of Neurology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors.forename: Z H
authors.initials: ZH
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Ji
authors.forename: W
authors.initials: W
authors.lastname: Shan
authors.forename: B
authors.initials: B
authors.lastname: Zeng
authors.forename: N
authors.initials: N
authors.lastname: Raksadawan
authors.forename: G M
authors.initials: GM
authors.lastname: Pastores
authors.forename: T
authors.initials: T
authors.lastname: Wisniewski
authors.forename: E H
authors.initials: EH
authors.lastname: Kolodny
mesh_terms: 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*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine