Elevated GDNF levels following viral vector-mediated gene transfer can increase neuronal death after stroke in rats
Previous studies have indicated that administration of glial cell line-derived neurotrophic factor (GDNF) counteracts neuronal death after stroke. However, in these studies damage was evaluated at most a few days after the insult. Here, we have explored the long-term consequences of two routes of GD...
Main Authors: | , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2003-12-01
|
Series: | Neurobiology of Disease |
Subjects: | |
Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996103001542 |
id |
doaj-b096a0c7f0a74640b68ad81c6b7e4b66 |
---|---|
record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Andreas Arvidsson Deniz Kirik Cecilia Lundberg Ronald J Mandel Gunnar Andsberg Zaal Kokaia Olle Lindvall |
spellingShingle |
Andreas Arvidsson Deniz Kirik Cecilia Lundberg Ronald J Mandel Gunnar Andsberg Zaal Kokaia Olle Lindvall Elevated GDNF levels following viral vector-mediated gene transfer can increase neuronal death after stroke in rats Neurobiology of Disease Glial cell line-derived neurotrophic factor Gene transfer Viral vector Stroke Cerebral ischemia Neuroprotection |
author_facet |
Andreas Arvidsson Deniz Kirik Cecilia Lundberg Ronald J Mandel Gunnar Andsberg Zaal Kokaia Olle Lindvall |
author_sort |
Andreas Arvidsson |
title |
Elevated GDNF levels following viral vector-mediated gene transfer can increase neuronal death after stroke in rats |
title_short |
Elevated GDNF levels following viral vector-mediated gene transfer can increase neuronal death after stroke in rats |
title_full |
Elevated GDNF levels following viral vector-mediated gene transfer can increase neuronal death after stroke in rats |
title_fullStr |
Elevated GDNF levels following viral vector-mediated gene transfer can increase neuronal death after stroke in rats |
title_full_unstemmed |
Elevated GDNF levels following viral vector-mediated gene transfer can increase neuronal death after stroke in rats |
title_sort |
elevated gdnf levels following viral vector-mediated gene transfer can increase neuronal death after stroke in rats |
publisher |
Elsevier |
series |
Neurobiology of Disease |
issn |
1095-953X |
publishDate |
2003-12-01 |
description |
Previous studies have indicated that administration of glial cell line-derived neurotrophic factor (GDNF) counteracts neuronal death after stroke. However, in these studies damage was evaluated at most a few days after the insult. Here, we have explored the long-term consequences of two routes of GDNF delivery to the rat striatum prior to stroke induced by 30 min of middle cerebral artery occlusion (MCAO): striatal transduction with a recombinant lentiviral vector or transduction of the substantia nigra with a recombinant adeno-associated viral vector and subsequent anterograde transport of GDNF to striatum. Despite high GDNF levels, stereological quantification of striatal neuron numbers revealed no protection at 5 or 8 weeks after MCAO. In fact, anterograde GDNF delivery exacerbated neuronal loss. Moreover, supply of GDNF did not alleviate the striatum-related behavioral deficits. Thus, we demonstrate that the actions of GDNF after stroke are more complex than previously believed and that high levels of this factor, which are neuroprotective in models of Parkinson's disease, can increase ischemic damage. Our findings also underscore the need for quantitative assessment of long-term neuronal survival and behavioral changes to evaluate the therapeutic potential of factors such as GDNF. |
topic |
Glial cell line-derived neurotrophic factor Gene transfer Viral vector Stroke Cerebral ischemia Neuroprotection |
url |
http://www.sciencedirect.com/science/article/pii/S0969996103001542 |
work_keys_str_mv |
AT andreasarvidsson elevatedgdnflevelsfollowingviralvectormediatedgenetransfercanincreaseneuronaldeathafterstrokeinrats AT denizkirik elevatedgdnflevelsfollowingviralvectormediatedgenetransfercanincreaseneuronaldeathafterstrokeinrats AT cecilialundberg elevatedgdnflevelsfollowingviralvectormediatedgenetransfercanincreaseneuronaldeathafterstrokeinrats AT ronaldjmandel elevatedgdnflevelsfollowingviralvectormediatedgenetransfercanincreaseneuronaldeathafterstrokeinrats AT gunnarandsberg elevatedgdnflevelsfollowingviralvectormediatedgenetransfercanincreaseneuronaldeathafterstrokeinrats AT zaalkokaia elevatedgdnflevelsfollowingviralvectormediatedgenetransfercanincreaseneuronaldeathafterstrokeinrats AT ollelindvall elevatedgdnflevelsfollowingviralvectormediatedgenetransfercanincreaseneuronaldeathafterstrokeinrats |
_version_ |
1724212160190480384 |
spelling |
doaj-b096a0c7f0a74640b68ad81c6b7e4b662021-03-20T04:48:47ZengElsevierNeurobiology of Disease1095-953X2003-12-01143542556Elevated GDNF levels following viral vector-mediated gene transfer can increase neuronal death after stroke in ratsAndreas Arvidsson0Deniz Kirik1Cecilia Lundberg2Ronald J Mandel3Gunnar Andsberg4Zaal Kokaia5Olle Lindvall6Section of Restorative Neurology, Wallenberg Neuroscience Center, BMC A11 SE-221 84 Lund, Sweden; Section of Neurobiology, Wallenberg Neuroscience Center, BMC A11 SE-221 84 Lund, Sweden; Department of Neuroscience and the Powell Gene Therapy Center, McKnight Brain Institute, University of Florida College of Medicine, P.O. Box 100244, Gainesville, FL 32610-0244, USASection of Restorative Neurology, Wallenberg Neuroscience Center, BMC A11 SE-221 84 Lund, Sweden; Section of Neurobiology, Wallenberg Neuroscience Center, BMC A11 SE-221 84 Lund, Sweden; Department of Neuroscience and the Powell Gene Therapy Center, McKnight Brain Institute, University of Florida College of Medicine, P.O. Box 100244, Gainesville, FL 32610-0244, USASection of Restorative Neurology, Wallenberg Neuroscience Center, BMC A11 SE-221 84 Lund, Sweden; Section of Neurobiology, Wallenberg Neuroscience Center, BMC A11 SE-221 84 Lund, Sweden; Department of Neuroscience and the Powell Gene Therapy Center, McKnight Brain Institute, University of Florida College of Medicine, P.O. Box 100244, Gainesville, FL 32610-0244, USASection of Restorative Neurology, Wallenberg Neuroscience Center, BMC A11 SE-221 84 Lund, Sweden; Section of Neurobiology, Wallenberg Neuroscience Center, BMC A11 SE-221 84 Lund, Sweden; Department of Neuroscience and the Powell Gene Therapy Center, McKnight Brain Institute, University of Florida College of Medicine, P.O. Box 100244, Gainesville, FL 32610-0244, USASection of Restorative Neurology, Wallenberg Neuroscience Center, BMC A11 SE-221 84 Lund, Sweden; Section of Neurobiology, Wallenberg Neuroscience Center, BMC A11 SE-221 84 Lund, Sweden; Department of Neuroscience and the Powell Gene Therapy Center, McKnight Brain Institute, University of Florida College of Medicine, P.O. Box 100244, Gainesville, FL 32610-0244, USASection of Restorative Neurology, Wallenberg Neuroscience Center, BMC A11 SE-221 84 Lund, Sweden; Section of Neurobiology, Wallenberg Neuroscience Center, BMC A11 SE-221 84 Lund, Sweden; Department of Neuroscience and the Powell Gene Therapy Center, McKnight Brain Institute, University of Florida College of Medicine, P.O. Box 100244, Gainesville, FL 32610-0244, USASection of Restorative Neurology, Wallenberg Neuroscience Center, BMC A11 SE-221 84 Lund, Sweden; Section of Neurobiology, Wallenberg Neuroscience Center, BMC A11 SE-221 84 Lund, Sweden; Department of Neuroscience and the Powell Gene Therapy Center, McKnight Brain Institute, University of Florida College of Medicine, P.O. Box 100244, Gainesville, FL 32610-0244, USAPrevious studies have indicated that administration of glial cell line-derived neurotrophic factor (GDNF) counteracts neuronal death after stroke. However, in these studies damage was evaluated at most a few days after the insult. Here, we have explored the long-term consequences of two routes of GDNF delivery to the rat striatum prior to stroke induced by 30 min of middle cerebral artery occlusion (MCAO): striatal transduction with a recombinant lentiviral vector or transduction of the substantia nigra with a recombinant adeno-associated viral vector and subsequent anterograde transport of GDNF to striatum. Despite high GDNF levels, stereological quantification of striatal neuron numbers revealed no protection at 5 or 8 weeks after MCAO. In fact, anterograde GDNF delivery exacerbated neuronal loss. Moreover, supply of GDNF did not alleviate the striatum-related behavioral deficits. Thus, we demonstrate that the actions of GDNF after stroke are more complex than previously believed and that high levels of this factor, which are neuroprotective in models of Parkinson's disease, can increase ischemic damage. Our findings also underscore the need for quantitative assessment of long-term neuronal survival and behavioral changes to evaluate the therapeutic potential of factors such as GDNF.http://www.sciencedirect.com/science/article/pii/S0969996103001542Glial cell line-derived neurotrophic factorGene transferViral vectorStrokeCerebral ischemiaNeuroprotection |