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Rescue and sprouting of motoneurons following ventral root avulsion and reimplantation combined with intraspinal adeno-associated viral vector-mediated expression of glial cell line-derived neurotrophic factor or brain-derived neurotrophic factor

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Bibliographic Details
Title: Rescue and sprouting of motoneurons following ventral root avulsion and reimplantation combined with intraspinal adeno-associated viral vector-mediated expression of glial cell line-derived neurotrophic factor or brain-derived neurotrophic factor
Authors: Blits, Bas, Carlstedt, Thomas P., Ruitenberg, Marc Jan, de Winter, Fred, Hermens, Wim T. J. M. C., Dijkhuizen, Paul A., Claasens, Jill W. C., Eggers, Ruben, van der Sluis, Ronald, Tenenbaum, Liliane, Boer, Gerard J., Verhaagen, Joost
Source: Experimental Neurology. 189:303-316
Publisher Information: Elsevier BV, 2004.
Publication Year: 2004
Subject Terms: Viral vectors, Male, 0301 basic medicine, Nerve Growth Factors -- genetics, Wistar, Recovery of Function -- genetics, 0601 Biochemistry and Cell Biology, 0302 clinical medicine, Spinal Cord -- pathology, Non-U.S. Gov't, Radiculopathy, Motor Neurons, Spinal cord, Radiculopathy -- pathology, Lumbar Vertebrae, Neuronal Plasticity, Sciatic Nerve -- physiology, Nerve Regeneration -- genetics, Gene Transfer Techniques, Spinal Nerve Roots -- surgery, Sciences bio-médicales et agricoles, GDNF, Sciatic Nerve, Motoneuron, Spinal Nerve Roots -- pathology, Spinal Cord, Neuroregeneration, Spinal Nerve Roots, Brain-Derived Neurotrophic Factor -- genetics, Spinal Cord -- metabolism, Genetic Vectors, Growth Cones, Neurotrophic factor, Spinal Nerve Roots -- injuries, Research Support, 03 medical and health sciences, Journal Article, Animals, Growth Cones -- ultrastructure, Neuronal Plasticity -- genetics, Glial Cell Line-Derived Neurotrophic Factor, Nerve Growth Factors, Rats, Wistar, Sciatic Nerve -- cytology, Brain-Derived Neurotrophic Factor, Recovery of Function, Nerve Regeneration, Rats, BDNF, Radiculopathy -- metabolism, Motor Neurons -- cytology, Radiculopathy -- therapy, Motor Neurons -- metabolism, Growth Cones -- metabolism
Description: Following avulsion of a spinal ventral root, motoneurons that project through the avulsed root are axotomized. Avulsion between, for example, L2 and L6 leads to denervation of hind limb muscles. Reimplantation of an avulsed root directed to the motoneuron pool resulted in re-ingrowth of some motor axons. However, most motoneurons display retrograde atrophy and subsequently die. Two neurotrophic factors, glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), promote the survival of motoneurons after injury. The long-term delivery of these neurotrophic factors to the motoneurons in the ventral horn of the spinal cord is problematic. One strategy to improve the outcome of the neurosurgical reinsertion of the ventral root following avulsion would involve gene transfer with adeno-associated viral (AAV) vectors encoding these neurotrophic factors near the denervated motoneuron pool. Here, we show that AAV-mediated overexpression of GDNF and BDNF in the spinal cord persisted for at least 16 weeks. At both 1 and 4 months post-lesion AAV-BDNF- and -GDNF-treated animals showed an increased survival of motoneurons, the effect being more prominent at 1 month. AAV vector-mediated overexpression of neurotrophins also promoted the formation of a network of motoneuron fibers in the ventral horn at the avulsed side, but motoneurons failed to extent axons into the reinserted L4 root towards the sciatic nerve nor to improve functional recovery of the hind limbs. This suggests that high levels of neurotrophic factors in the ventral horn promote sprouting, but prevent directional growth of axons of a higher number of surviving motoneurons into the implanted root.
Document Type: Article
File Description: 1 full-text file(s): application/pdf
Language: English
ISSN: 0014-4886
DOI: 10.1016/j.expneurol.2004.05.014
Access URL: https://pubmed.ncbi.nlm.nih.gov/15380481
http://www.sciencedirect.com/science/article/pii/S0014488604001979
https://pubmed.ncbi.nlm.nih.gov/15380481/
https://difusion.ulb.ac.be/vufind/Record/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/58479/Details
https://europepmc.org/abstract/MED/15380481
https://www.ncbi.nlm.nih.gov/pubmed/15380481
https://core.ac.uk/display/153335465
Rights: Elsevier TDM
Accession Number: edsair.doi.dedup.....e8373d5eeefbd3889042f52320606c69
Database: OpenAIRE
Description
Abstract:Following avulsion of a spinal ventral root, motoneurons that project through the avulsed root are axotomized. Avulsion between, for example, L2 and L6 leads to denervation of hind limb muscles. Reimplantation of an avulsed root directed to the motoneuron pool resulted in re-ingrowth of some motor axons. However, most motoneurons display retrograde atrophy and subsequently die. Two neurotrophic factors, glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), promote the survival of motoneurons after injury. The long-term delivery of these neurotrophic factors to the motoneurons in the ventral horn of the spinal cord is problematic. One strategy to improve the outcome of the neurosurgical reinsertion of the ventral root following avulsion would involve gene transfer with adeno-associated viral (AAV) vectors encoding these neurotrophic factors near the denervated motoneuron pool. Here, we show that AAV-mediated overexpression of GDNF and BDNF in the spinal cord persisted for at least 16 weeks. At both 1 and 4 months post-lesion AAV-BDNF- and -GDNF-treated animals showed an increased survival of motoneurons, the effect being more prominent at 1 month. AAV vector-mediated overexpression of neurotrophins also promoted the formation of a network of motoneuron fibers in the ventral horn at the avulsed side, but motoneurons failed to extent axons into the reinserted L4 root towards the sciatic nerve nor to improve functional recovery of the hind limbs. This suggests that high levels of neurotrophic factors in the ventral horn promote sprouting, but prevent directional growth of axons of a higher number of surviving motoneurons into the implanted root.
ISSN:00144886
DOI:10.1016/j.expneurol.2004.05.014