Neuropathological and Behavioral Consequences of Adeno-Associated Viral Vector-Mediated Continuous Intrastriatal Neurotrophin Delivery in a Focal Ischemia Model in Rats
Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were continuously delivered to the striatum at biologically active levels via recombinant adeno-associated viral (rAAV) gene transfer 4–5 weeks prior to 30 min of middle cerebral artery occlusion (MCAO). The magnitude of the defi...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2002-03-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996101904565 |
| _version_ | 1818721382942375936 |
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| author | Gunnar Andsberg Zaal Kokaia Ronald L. Klein Nicholas Muzyczka Olle Lindvall Ronald J. Mandel |
| author_facet | Gunnar Andsberg Zaal Kokaia Ronald L. Klein Nicholas Muzyczka Olle Lindvall Ronald J. Mandel |
| author_sort | Gunnar Andsberg |
| collection | DOAJ |
| description | Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were continuously delivered to the striatum at biologically active levels via recombinant adeno-associated viral (rAAV) gene transfer 4–5 weeks prior to 30 min of middle cerebral artery occlusion (MCAO). The magnitude of the deficits in a battery of behavioral tests designed to assess striatal function was highly correlated to the extent of ischemic damage determined by unbiased stereological estimations of striatal neuron numbers. The delivery of neurotrophins lead to mild functional improvements in the ischemia-induced motor impairments assessed 3–5 weeks after the insult, in agreement with a small but significant increase of the survival of dorsolateral striatal neurons. Detailed phenotypic analysis demonstrated that the parvalbumin-containing interneurons were spared to a greater extent by the neurotrophin treatment as compared to the projection neurons, which agreed with the specificity for interneuron transduction by the rAAV vector. These data show the advantage of the never previously performed combination of precise quantification of the ischemia-induced neuropathology along with detailed behavioural analysis for assessing neuroprotection after stroke. We observe that intrastriatal delivery of NGF and BDNF using a viral vector system can mitigate, albeit only moderately, neuronal death following stroke, which leads to detectable functional sparing. |
| first_indexed | 2024-12-17T20:37:51Z |
| format | Article |
| id | doaj.art-4ec2ae1e8aae49d5a848503cfcb63b8e |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-17T20:37:51Z |
| publishDate | 2002-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-4ec2ae1e8aae49d5a848503cfcb63b8e2022-12-21T21:33:23ZengElsevierNeurobiology of Disease1095-953X2002-03-0192187204Neuropathological and Behavioral Consequences of Adeno-Associated Viral Vector-Mediated Continuous Intrastriatal Neurotrophin Delivery in a Focal Ischemia Model in RatsGunnar Andsberg0Zaal Kokaia1Ronald L. Klein2Nicholas Muzyczka3Olle Lindvall4Ronald J. Mandel5Section of Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, BMC A-11 SE-221 84, Lund, Sweden; Department of Neuroscience, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244; Department of Pharmacology and Therapeutics, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244; Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244; The Powell Gene Therapy Center, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244Section of Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, BMC A-11 SE-221 84, Lund, Sweden; Department of Neuroscience, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244; Department of Pharmacology and Therapeutics, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244; Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244; The Powell Gene Therapy Center, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244Section of Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, BMC A-11 SE-221 84, Lund, Sweden; Department of Neuroscience, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244; Department of Pharmacology and Therapeutics, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244; Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244; The Powell Gene Therapy Center, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244Section of Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, BMC A-11 SE-221 84, Lund, Sweden; Department of Neuroscience, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244; Department of Pharmacology and Therapeutics, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244; Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244; The Powell Gene Therapy Center, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244Section of Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, BMC A-11 SE-221 84, Lund, Sweden; Department of Neuroscience, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244; Department of Pharmacology and Therapeutics, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244; Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244; The Powell Gene Therapy Center, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244Section of Restorative Neurology, Wallenberg Neuroscience Center, University Hospital, BMC A-11 SE-221 84, Lund, Sweden; Department of Neuroscience, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244; Department of Pharmacology and Therapeutics, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244; Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244; The Powell Gene Therapy Center, University of Florida College of Medicine, P.O. Box 100244, Gainesville, Florida, 32610-0244Nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were continuously delivered to the striatum at biologically active levels via recombinant adeno-associated viral (rAAV) gene transfer 4–5 weeks prior to 30 min of middle cerebral artery occlusion (MCAO). The magnitude of the deficits in a battery of behavioral tests designed to assess striatal function was highly correlated to the extent of ischemic damage determined by unbiased stereological estimations of striatal neuron numbers. The delivery of neurotrophins lead to mild functional improvements in the ischemia-induced motor impairments assessed 3–5 weeks after the insult, in agreement with a small but significant increase of the survival of dorsolateral striatal neurons. Detailed phenotypic analysis demonstrated that the parvalbumin-containing interneurons were spared to a greater extent by the neurotrophin treatment as compared to the projection neurons, which agreed with the specificity for interneuron transduction by the rAAV vector. These data show the advantage of the never previously performed combination of precise quantification of the ischemia-induced neuropathology along with detailed behavioural analysis for assessing neuroprotection after stroke. We observe that intrastriatal delivery of NGF and BDNF using a viral vector system can mitigate, albeit only moderately, neuronal death following stroke, which leads to detectable functional sparing.http://www.sciencedirect.com/science/article/pii/S0969996101904565nerve growth factorsviral vectorstrokeischemiabehaviorstriatum |
| spellingShingle | Gunnar Andsberg Zaal Kokaia Ronald L. Klein Nicholas Muzyczka Olle Lindvall Ronald J. Mandel Neuropathological and Behavioral Consequences of Adeno-Associated Viral Vector-Mediated Continuous Intrastriatal Neurotrophin Delivery in a Focal Ischemia Model in Rats Neurobiology of Disease nerve growth factors viral vector stroke ischemia behavior striatum |
| title | Neuropathological and Behavioral Consequences of Adeno-Associated Viral Vector-Mediated Continuous Intrastriatal Neurotrophin Delivery in a Focal Ischemia Model in Rats |
| title_full | Neuropathological and Behavioral Consequences of Adeno-Associated Viral Vector-Mediated Continuous Intrastriatal Neurotrophin Delivery in a Focal Ischemia Model in Rats |
| title_fullStr | Neuropathological and Behavioral Consequences of Adeno-Associated Viral Vector-Mediated Continuous Intrastriatal Neurotrophin Delivery in a Focal Ischemia Model in Rats |
| title_full_unstemmed | Neuropathological and Behavioral Consequences of Adeno-Associated Viral Vector-Mediated Continuous Intrastriatal Neurotrophin Delivery in a Focal Ischemia Model in Rats |
| title_short | Neuropathological and Behavioral Consequences of Adeno-Associated Viral Vector-Mediated Continuous Intrastriatal Neurotrophin Delivery in a Focal Ischemia Model in Rats |
| title_sort | neuropathological and behavioral consequences of adeno associated viral vector mediated continuous intrastriatal neurotrophin delivery in a focal ischemia model in rats |
| topic | nerve growth factors viral vector stroke ischemia behavior striatum |
| url | http://www.sciencedirect.com/science/article/pii/S0969996101904565 |
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