title: Neuroprotective potential of pleiotrophin overexpression in the striatonigral pathway compared with overexpression in both the striatonigral and nigrostriatal pathways.
abstract: Intrastriatal injection of recombinant adeno-associated viral vector serotype 2/1 (rAAV2/1) to overexpress the neurotrophic factor pleiotrophin (PTN) provides neuroprotection for tyrosine hydroxylase immunoreactive (THir) neurons in the substantia nigra pars compacta (SNpc), increases THir neurite density in the striatum (ST) and reverses functional deficits in forepaw use following 6-hydroxydopamine (6-OHDA) toxic insult. Glial cell line-derived neurotrophic factor (GDNF) gene transfer studies suggest that optimal neuroprotection is dependent on the site of nigrostriatal overexpression. The present study was conducted to determine whether enhanced neuroprotection could be accomplished via simultaneous rAAV2/1 PTN injections into the ST and SN compared with ST injections alone. Rats were unilaterally injected in the ST alone or injected in both the ST and SN with rAAV2/1 expressing either PTN or control vector. Four weeks later, all rats received intrastriatal injections of 6-OHDA. Rats were euthanized 6 or 16 weeks relative to 6-OHDA injection. A novel selective total enumeration method to estimate nigral THir neuron survival was validated to maintain the accuracy of stereological assessment. Long-term nigrostriatal neuroprotection and functional benefits were only observed in rats in which rAAV2/1 PTN was injected into the ST alone. Results suggest that superior preservation of the nigrostriatal system is provided by PTN overexpression delivered to the ST and restricted to the ST and SN pars reticulata and is not improved with overexpression of PTN within SNpc neurons.
authors.affiliation: 1] Graduate Program in Neuroscience, University of Cincinnati, Cincinnati, OH, USA [2] Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Gombash
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: F P
authors.initials: FP
authors.lastname: Manfredsson
authors.affiliation: Department of Neuroscience, Powell Gene Therapy Center, McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Mandel
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Collier
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Fischer
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Kemp
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: N M
authors.initials: NM
authors.lastname: Kuhn
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: S L
authors.initials: SL
authors.lastname: Wohlgenant
authors.affiliation: Departments of Psychology and Neurology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Fleming
authors.affiliation: Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Sortwell
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003342:Corpus Striatum / Q000378:metabolism*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage; D008297:Male; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000628:therapy*; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000494:pharmacology; D016627:Oxidopamine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D018696:Neuroprotective Agents; C066845:pleiotrophin; D016627:Oxidopamine