Comparison of the capability of GDNF, BDNF, or both, to protect nigrostriatal neurons in a rat model of Parkinson's disease

Both glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) can protect nigrostriatal dopaminergic neurons from neurotoxins in rodent and monkey models of Parkinson's disease (PD). These two neurotrophic factors are usually tested individually. This study was designed to compare GDNF, BDNF, or both, for their capabilities to correct behavioral deficits and protect nigrostriatal dopaminergic neurons in a rat model of PD. Gene transfer used a helper virus-free Herpes Simplex Virus (HSV-1) vector system and a modified neurofilament heavy gene promoter that supports long-term expression in forebrain neurons. Rats received unilateral intrastriatal injections of HSV-1 vectors that express either GDNF or BDNF, or both vectors, followed by intrastriatal injections of 6-hydroxydopamine (6-OHDA). Recombinant GDNF or BDNF was detected in striatal neurons in rats sacrificed at 7 months after gene transfer. Of note, GDNF was significantly more effective than BDNF for both correcting behavioral deficits and protecting nigrostriatal dopaminergic neurons. Expression of both neurotrophic factors was no more effective than expression of only GDNF. These results suggest that GDNF is more effective than BDNF for correcting the rat model of PD, and that there are no detectable benefits from expressing both of these neurotrophic factors.

[1]  B J Hoffer,et al.  Morphological and functional effects of intranigrally administered GDNF in normal rhesus monkeys , 1995, The Journal of comparative neurology.

[2]  R. J. Mullen,et al.  NeuN, a neuronal specific nuclear protein in vertebrates. , 1992, Development.

[3]  R. Duvoisin,et al.  Treatment of parkinsonism with levodopa. , 1969, Archives of neurology.

[4]  A. Björklund,et al.  Aberrant Sprouting and Downregulation of Tyrosine Hydroxylase in Lesioned Nigrostriatal Dopamine Neurons Induced by Long-Lasting Overexpression of Glial Cell Line Derived Neurotrophic Factor in the Striatum by Lentiviral Gene Transfer , 2002, Experimental Neurology.

[5]  A. Björklund,et al.  Long-Term rAAV-Mediated Gene Transfer of GDNF in the Rat Parkinson's Model: Intrastriatal But Not Intranigral Transduction Promotes Functional Regeneration in the Lesioned Nigrostriatal System , 2000, The Journal of Neuroscience.

[6]  A. Björklund,et al.  Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of l-dopa using rAAV-mediated gene transfer , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[7]  A. Björklund,et al.  Neural transplantation for the treatment of Parkinson's disease , 2003, The Lancet Neurology.

[8]  R. Wurtman,et al.  Partial lesions of the dopaminergic nigrostriatal system in rat brain: biochemical characterization , 1980, Brain Research.

[9]  J. Haycock,et al.  l-Dopa and Dopamine-Producing Gene Cassettes for Gene Therapy Approaches to Parkinson's Disease , 1997, Experimental Neurology.

[10]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[11]  J. Kordower.  In vivo gene delivery of glial cell line–derived neurotrophic factor for Parkinson's disease , 2003, Annals of neurology.

[12]  J. Naegele,et al.  Long-Term Behavioral Recovery in Parkinsonian Rats by an HSV Vector Expressing Tyrosine Hydroxylase , 1994, Science.

[13]  D. Goldstein,et al.  Correction of a rat model of Parkinson's disease by coexpression of tyrosine hydroxylase and aromatic amino acid decarboxylase from a helper virus-free herpes simplex virus type 1 vector. , 2003, Human gene therapy.

[14]  J. Bloch,et al.  Lentiviral Gene Transfer to the Nonhuman Primate Brain , 1999, Experimental Neurology.

[15]  J. Bloch,et al.  Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease. , 2000, Science.

[16]  M. Levivier,et al.  Intrastriatal implantation of fibroblasts genetically engineered to produce brain-derived neurotrophic factor prevents degeneration of dopaminergic neurons in a rat model of Parkinson's disease , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[17]  D. Kirik,et al.  Long‐term striatal overexpression of GDNF selectively downregulates tyrosine hydroxylase in the intact nigrostriatal dopamine system , 2003, The European journal of neuroscience.

[18]  Howard J. Federoff,et al.  Regulated Release and Polarized Localization of Brain-Derived Neurotrophic Factor in Hippocampal Neurons , 1996, Molecular and Cellular Neuroscience.

[19]  Guo-Rong Zhang,et al.  Coexpression of tyrosine hydroxylase, GTP cyclohydrolase I, aromatic amino acid decarboxylase, and vesicular monoamine transporter 2 from a helper virus-free herpes simplex virus type 1 vector supports high-level, long-term biochemical and behavioral correction of a rat model of Parkinson's disease. , 2004, Human gene therapy.

[20]  P. Wild,et al.  Helper virus-free transfer of herpes simplex virus type 1 plasmid vectors into neural cells , 1996, Journal of virology.

[21]  D. Pfaff,et al.  Inflammatory effects of gene transfer into the CNS with defective HSV-1 vectors. , 1994, Gene therapy.

[22]  S. Wiegand,et al.  Brain-derived neurotrophic factor augments rotational behavior and nigrostriatal dopamine turnover in vivo. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[23]  J. Lile,et al.  GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. , 1993, Science.

[24]  W Zhang,et al.  A tyrosine hydroxylase-neurofilament chimeric promoter enhances long-term expression in rat forebrain neurons from helper virus-free HSV-1 vectors. , 2000, Brain research. Molecular brain research.

[25]  A. Geller,et al.  General strategy for constructing large HSV-1 plasmid vectors that co-express multiple genes. , 2001, BioTechniques.

[26]  D. Brooks,et al.  Direct brain infusion of glial cell line–derived neurotrophic factor in Parkinson disease , 2003, Nature Medicine.

[27]  R. Neve,et al.  An HSV‐1 Vector Containing the Rat Tyrosine Hydroxylase Promoter Enhances Both Long‐Term and Cell Type‐Specific Expression in the Midbrain , 1997, Journal of neurochemistry.

[28]  B. Davidson,et al.  Dopaminergic Neurons Protected from Degeneration by GDNF Gene Therapy , 1997, Science.

[29]  P. Lang,et al.  Generation of high-titer defective HSV-1 vectors using an IE 2 deletion mutant and quantitative study of expression in cultured cortical cells. , 1996, BioTechniques.

[30]  G. Yancopoulos,et al.  BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra , 1991, Nature.

[31]  A. Björklund,et al.  Overexpression of Glial Cell Line-Derived Neurotrophic Factor Using a Lentiviral Vector Induces Time- and Dose-Dependent Downregulation of Tyrosine Hydroxylase in the Intact Nigrostriatal Dopamine System , 2004, The Journal of Neuroscience.

[32]  A. Björklund,et al.  Localized striatal delivery of GDNF as a treatment for Parkinson disease , 2004, Nature Neuroscience.

[33]  R. Ridley,et al.  Continuous Low-Level Glial Cell Line-Derived Neurotrophic Factor Delivery Using Recombinant Adeno-Associated Viral Vectors Provides Neuroprotection and Induces Behavioral Recovery in a Primate Model of Parkinson's Disease , 2005, The Journal of Neuroscience.

[34]  X. Breakefield,et al.  Astrocytes retrovirally transduced with BDNF elicit behavioral improvement in a rat model of Parkinson's disease , 1995, Brain Research.

[35]  A. Geller,et al.  Enhanced reporter gene expression in the rat brain from helper virus-free HSV-1 vectors packaged in the presence of specific mutated HSV-1 proteins that affect the virion. , 2001, Brain research. Molecular brain research.

[36]  N. Muzyczka,et al.  Prevention of 6-hydroxydopamine-induced rotational behavior by BDNF somatic gene transfer , 1999, Brain Research.

[37]  B. Hoffer,et al.  Functional recovery in parkinsonian monkeys treated with GDNF , 1996, Nature.

[38]  A. Geller,et al.  Improved titers for helper virus-free herpes simplex virus type 1 plasmid vectors by optimization of the packaging protocol and addition of noninfectious herpes simplex virus-related particles (previral DNA replication enveloped particles) to the packaging procedure. , 1999, Human gene therapy.

[39]  M. A. Hardwicke,et al.  Evidence that the herpes simplex virus immediate early protein ICP27 acts post-transcriptionally during infection to regulate gene expression. , 1992, Virology.

[40]  R. Roth,et al.  Biochemical and behavioral recovery in a rodent model of Parkinson's disease following stereotactic implantation of dopamine-containing liposomes , 1992, Experimental Neurology.

[41]  S. Wiegand,et al.  Efficacy of Brain‐Derived Neurotrophic Factor and Neurotrophin‐3 on Neurochemical and Behavioral Deficits Associated with Partial Nigrostriatal Dopamine Lesions , 1994, Journal of neurochemistry.