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Behavioral and cellular protection of rat dopaminergic neurons by an adenoviral vector encoding glial cell line-derived neurotrophic factor.
Exp Neurol. 1998 Dec; 154(2):261-75.EN

Abstract

Previously, we observed that an adenoviral (Ad) vector encoding human glial cell line-derived neurotrophic factor (GDNF), injected near the rat substantia nigra (SN), protects SN dopaminergic (DA) neuronal soma from 6-hydroxydopamine (6-OHDA)-induced degeneration. In the present study, the effects of Ad GDNF injected into the striatum, the site of DA nerve terminals, were assessed in the same lesion model. So that effects on cell survival could be assessed without relying on DA phenotypic markers, fluorogold (FG) was infused bilaterally into striatae to retrogradely label DA neurons. Ad GDNF or control treatment (Ad mGDNF, encoding a deletion mutant GDNF, Ad lacZ, vehicle, or no injection) was injected unilaterally into the striatum near one FG site. Progressive degeneration of DA neurons was initiated 7 days later by unilateral injection of 6-OHDA at this FG site. At 42 days after 6-OHDA, Ad GDNF prevented the death of 40% of susceptible DA neurons that projected to the lesion site. Ad GDNF prevented the development of behavioral asymmetries which depend on striatal dopamine, including limb use asymmetries during spontaneous movements along vertical surfaces and amphetamine-induced rotation. Both behavioral asymmetries were exhibited by control-treated, lesioned rats. Interestingly, these behavioral protections occurred in the absence of an increase in the density of DA nerve fibers in the striatum of Ad GDNF-treated rats. ELISA measurements of transgene proteins showed that nanogram quantities of GDNF and lacZ transgene were present in the striatum for 7 weeks, and picogram quantities of GDNF in the SN due to retrograde transport of vector and/or transgene protein. These studies demonstrate that Ad GDNF can sustain increased levels of biosynthesized GDNF in the terminal region of DA neurons for at least 7 weeks and that this GDNF slows the degeneration of DA neurons and prevents the appearance of dopamine dependent motor asymmetries in a rat model of Parkinson's disease (PD). GDNF gene therapy targeted to the striatum, a more surgically accessible site than the SN, may be clinically applicable to humans with PD.

Authors+Show Affiliations

Department of Neurobiology and Anatomy, University of Rochester, School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York, 14642, USA. dlcl@gene.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

9878166

Citation

Choi-Lundberg, D L., et al. "Behavioral and Cellular Protection of Rat Dopaminergic Neurons By an Adenoviral Vector Encoding Glial Cell Line-derived Neurotrophic Factor." Experimental Neurology, vol. 154, no. 2, 1998, pp. 261-75.
Choi-Lundberg DL, Lin Q, Schallert T, et al. Behavioral and cellular protection of rat dopaminergic neurons by an adenoviral vector encoding glial cell line-derived neurotrophic factor. Exp Neurol. 1998;154(2):261-75.
Choi-Lundberg, D. L., Lin, Q., Schallert, T., Crippens, D., Davidson, B. L., Chang, Y. N., Chiang, Y. L., Qian, J., Bardwaj, L., & Bohn, M. C. (1998). Behavioral and cellular protection of rat dopaminergic neurons by an adenoviral vector encoding glial cell line-derived neurotrophic factor. Experimental Neurology, 154(2), 261-75.
Choi-Lundberg DL, et al. Behavioral and Cellular Protection of Rat Dopaminergic Neurons By an Adenoviral Vector Encoding Glial Cell Line-derived Neurotrophic Factor. Exp Neurol. 1998;154(2):261-75. PubMed PMID: 9878166.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Behavioral and cellular protection of rat dopaminergic neurons by an adenoviral vector encoding glial cell line-derived neurotrophic factor. AU - Choi-Lundberg,D L, AU - Lin,Q, AU - Schallert,T, AU - Crippens,D, AU - Davidson,B L, AU - Chang,Y N, AU - Chiang,Y L, AU - Qian,J, AU - Bardwaj,L, AU - Bohn,M C, PY - 1999/1/8/pubmed PY - 1999/1/8/medline PY - 1999/1/8/entrez SP - 261 EP - 75 JF - Experimental neurology JO - Exp Neurol VL - 154 IS - 2 N2 - Previously, we observed that an adenoviral (Ad) vector encoding human glial cell line-derived neurotrophic factor (GDNF), injected near the rat substantia nigra (SN), protects SN dopaminergic (DA) neuronal soma from 6-hydroxydopamine (6-OHDA)-induced degeneration. In the present study, the effects of Ad GDNF injected into the striatum, the site of DA nerve terminals, were assessed in the same lesion model. So that effects on cell survival could be assessed without relying on DA phenotypic markers, fluorogold (FG) was infused bilaterally into striatae to retrogradely label DA neurons. Ad GDNF or control treatment (Ad mGDNF, encoding a deletion mutant GDNF, Ad lacZ, vehicle, or no injection) was injected unilaterally into the striatum near one FG site. Progressive degeneration of DA neurons was initiated 7 days later by unilateral injection of 6-OHDA at this FG site. At 42 days after 6-OHDA, Ad GDNF prevented the death of 40% of susceptible DA neurons that projected to the lesion site. Ad GDNF prevented the development of behavioral asymmetries which depend on striatal dopamine, including limb use asymmetries during spontaneous movements along vertical surfaces and amphetamine-induced rotation. Both behavioral asymmetries were exhibited by control-treated, lesioned rats. Interestingly, these behavioral protections occurred in the absence of an increase in the density of DA nerve fibers in the striatum of Ad GDNF-treated rats. ELISA measurements of transgene proteins showed that nanogram quantities of GDNF and lacZ transgene were present in the striatum for 7 weeks, and picogram quantities of GDNF in the SN due to retrograde transport of vector and/or transgene protein. These studies demonstrate that Ad GDNF can sustain increased levels of biosynthesized GDNF in the terminal region of DA neurons for at least 7 weeks and that this GDNF slows the degeneration of DA neurons and prevents the appearance of dopamine dependent motor asymmetries in a rat model of Parkinson's disease (PD). GDNF gene therapy targeted to the striatum, a more surgically accessible site than the SN, may be clinically applicable to humans with PD. SN - 0014-4886 UR - https://www.unboundmedicine.com/medline/citation/9878166/Behavioral_and_cellular_protection_of_rat_dopaminergic_neurons_by_an_adenoviral_vector_encoding_glial_cell_line_derived_neurotrophic_factor_ DB - PRIME DP - Unbound Medicine ER -