Neuroprotective potential of pleiotrophin overexpression in the striatonigral pathway compared with overexpression in both the striatonigral and nigrostriatal pathways
| Autor: | Susan L. Wohlgenant, Timothy J. Collier, Fredric P. Manfredsson, D L Fischer, Christopher J. Kemp, Sara E. Gombash, Sheila M. Fleming, Caryl E. Sortwell, N M Kuhn, Ronald J. Mandel |
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| Rok vydání: | 2014 |
| Předmět: |
Male
medicine.medical_specialty Genetic Vectors Substantia nigra Striatum Pleiotrophin Neuroprotection Article Cell Line Rats Sprague-Dawley Transduction Genetic Neurotrophic factors Internal medicine Genetics medicine Glial cell line-derived neurotrophic factor Animals Oxidopamine Molecular Biology biology Pars compacta Neurodegenerative Diseases Genetic Therapy Dependovirus Corpus Striatum Rats Substantia Nigra Disease Models Animal Neuroprotective Agents Endocrinology nervous system biology.protein Cytokines Molecular Medicine Carrier Proteins Pars reticulata |
| Zdroj: | Gene Therapy. 21:682-693 |
| ISSN: | 1476-5462 0969-7128 |
| DOI: | 10.1038/gt.2014.42 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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