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Astrocyte delivery of glial cell line-derived neurotrophic factor in a mouse model of Parkinson's disease.
Exp Neurol. 2002 Apr; 174(2):230-42.EN

Abstract

Primary astrocytes were genetically modified ex vivo to express recombinant glial cell line-derived neurotrophic factor (GDNF) and subsequently were tested for their ability to provide neuroprotection to dopaminergic neurons in a 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease. A replication-defective retrovirus was constructed, which contained the rat GDNF sequence and a sequence encoding a beta-galactosidase (beta-gal)/neomycin phosphotransferase fusion protein, linked via an internal ribosomal entry site. Murine astrocytes transduced with this vector secreted GDNF into the culture media at the rate of 115 +/- 34 pg/24 h/10(5) cells and expressed cytoplasmic beta-gal, whereas control nontransduced astrocytes were negative for GDNF production and cytoplasmic beta-gal expression. Mice that received implants of GDNF-producing astrocytes into the striatum or nigra displayed elevated levels of GDNF compared to mice that received control nontransduced astrocytes. In addition, tissue content of GDNF was increased bilaterally and in brain regions both proximal and distal to the graft, even though astrocyte migration away from the graft site did not occur. Importantly, GDNF-producing astrocytes provided marked neuroprotection of nigral dopaminergic perikarya, and partial protection of striatal dopaminergic fibers, when implanted into the midbrain 6 days prior to a retrograde 6-OHDA lesion, as assessed by tyrosine hydroxylase immunohistochemistry. Similarly, GDNF-producing astrocytes prevented the acquisition of amphetamine-induced rotational behavior in 6-OHDA-treated mice and completely prevented dopamine depletion within the substantia nigra, as assessed by high-performance liquid chromatography. These results indicate that continuous exposure to low levels of GDNF provided by transgenic astrocytes provides marked neuroprotection of nigral dopaminergic neurons. (c)2002 Elsevier Science (USA).

Authors+Show Affiliations

Department of Neurosciences, University of New Mexico School of Medicine, Albuquerque, New Mexico, 87131, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11922664

Citation

Cunningham, Lee Anna, and Chunyan Su. "Astrocyte Delivery of Glial Cell Line-derived Neurotrophic Factor in a Mouse Model of Parkinson's Disease." Experimental Neurology, vol. 174, no. 2, 2002, pp. 230-42.
Cunningham LA, Su C. Astrocyte delivery of glial cell line-derived neurotrophic factor in a mouse model of Parkinson's disease. Exp Neurol. 2002;174(2):230-42.
Cunningham, L. A., & Su, C. (2002). Astrocyte delivery of glial cell line-derived neurotrophic factor in a mouse model of Parkinson's disease. Experimental Neurology, 174(2), 230-42.
Cunningham LA, Su C. Astrocyte Delivery of Glial Cell Line-derived Neurotrophic Factor in a Mouse Model of Parkinson's Disease. Exp Neurol. 2002;174(2):230-42. PubMed PMID: 11922664.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Astrocyte delivery of glial cell line-derived neurotrophic factor in a mouse model of Parkinson's disease. AU - Cunningham,Lee Anna, AU - Su,Chunyan, PY - 2002/4/2/pubmed PY - 2002/5/3/medline PY - 2002/4/2/entrez SP - 230 EP - 42 JF - Experimental neurology JO - Exp Neurol VL - 174 IS - 2 N2 - Primary astrocytes were genetically modified ex vivo to express recombinant glial cell line-derived neurotrophic factor (GDNF) and subsequently were tested for their ability to provide neuroprotection to dopaminergic neurons in a 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease. A replication-defective retrovirus was constructed, which contained the rat GDNF sequence and a sequence encoding a beta-galactosidase (beta-gal)/neomycin phosphotransferase fusion protein, linked via an internal ribosomal entry site. Murine astrocytes transduced with this vector secreted GDNF into the culture media at the rate of 115 +/- 34 pg/24 h/10(5) cells and expressed cytoplasmic beta-gal, whereas control nontransduced astrocytes were negative for GDNF production and cytoplasmic beta-gal expression. Mice that received implants of GDNF-producing astrocytes into the striatum or nigra displayed elevated levels of GDNF compared to mice that received control nontransduced astrocytes. In addition, tissue content of GDNF was increased bilaterally and in brain regions both proximal and distal to the graft, even though astrocyte migration away from the graft site did not occur. Importantly, GDNF-producing astrocytes provided marked neuroprotection of nigral dopaminergic perikarya, and partial protection of striatal dopaminergic fibers, when implanted into the midbrain 6 days prior to a retrograde 6-OHDA lesion, as assessed by tyrosine hydroxylase immunohistochemistry. Similarly, GDNF-producing astrocytes prevented the acquisition of amphetamine-induced rotational behavior in 6-OHDA-treated mice and completely prevented dopamine depletion within the substantia nigra, as assessed by high-performance liquid chromatography. These results indicate that continuous exposure to low levels of GDNF provided by transgenic astrocytes provides marked neuroprotection of nigral dopaminergic neurons. (c)2002 Elsevier Science (USA). SN - 0014-4886 UR - https://www.unboundmedicine.com/medline/citation/11922664/Astrocyte_delivery_of_glial_cell_line_derived_neurotrophic_factor_in_a_mouse_model_of_Parkinson's_disease_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014488602978775 DB - PRIME DP - Unbound Medicine ER -