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Neuropathological and behavioral consequences of adeno-associated viral vector-mediated continuous intrastriatal neurotrophin delivery in a focal ischemia model in rats.

Andsberg, Gunnar LU ; Kokaia, Zaal LU ; Klein, Ronald L; Muzyczka, Nicholas; Lindvall, Olle LU and Mandel, Ronald J (2002) In Neurobiology of Disease 9(2). p.187-204
Abstract
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... (More)
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. (c)2002 Elsevier Science (USA). (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Adenoviridae/*genetics, Animal, Brain Ischemia/pathology/*therapy, Cell Survival, Brain-Derived Neurotrophic Factor/*genetics, Corpus Striatum/pathology, Gene Therapy, Genetic Vectors, Infarction, Middle Cerebral Artery/pathology/therapy, Interneurons/cytology, Behavior, Male, Nerve Growth Factor/*genetics, Rats, Phenotype
in
Neurobiology of Disease
volume
9
issue
2
pages
187 - 204
publisher
Elsevier
external identifiers
  • pmid:11895371
  • wos:000174485100007
  • scopus:0036199880
ISSN
0969-9961
DOI
10.1006/nbdi.2001.0456
language
English
LU publication?
yes
id
7505807c-8494-4f18-8a4c-93f0b0698b1a (old id 105997)
alternative location
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11895371&dopt=Abstract
date added to LUP
2007-07-23 15:36:15
date last changed
2017-12-10 03:39:58
@article{7505807c-8494-4f18-8a4c-93f0b0698b1a,
  abstract     = {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. (c)2002 Elsevier Science (USA).},
  author       = {Andsberg, Gunnar and Kokaia, Zaal and Klein, Ronald L and Muzyczka, Nicholas and Lindvall, Olle and Mandel, Ronald J},
  issn         = {0969-9961},
  keyword      = {Adenoviridae/*genetics,Animal,Brain Ischemia/pathology/*therapy,Cell Survival,Brain-Derived Neurotrophic Factor/*genetics,Corpus Striatum/pathology,Gene Therapy,Genetic Vectors,Infarction,Middle Cerebral Artery/pathology/therapy,Interneurons/cytology,Behavior,Male,Nerve Growth Factor/*genetics,Rats,Phenotype},
  language     = {eng},
  number       = {2},
  pages        = {187--204},
  publisher    = {Elsevier},
  series       = {Neurobiology of Disease},
  title        = {Neuropathological and behavioral consequences of adeno-associated viral vector-mediated continuous intrastriatal neurotrophin delivery in a focal ischemia model in rats.},
  url          = {http://dx.doi.org/10.1006/nbdi.2001.0456},
  volume       = {9},
  year         = {2002},
}