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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.
Exp Neurol. 2004 Oct; 189(2):303-16.EN

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.

Authors+Show Affiliations

Graduate School Neurosciences Amsterdam, Netherlands Institute for Brain Research, 1105 AZ Amsterdam, The Netherlands.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15380481

Citation

Blits, Bas, et al. "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." Experimental Neurology, vol. 189, no. 2, 2004, pp. 303-16.
Blits B, Carlstedt TP, Ruitenberg MJ, et al. 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. Exp Neurol. 2004;189(2):303-16.
Blits, B., Carlstedt, T. P., Ruitenberg, M. J., de Winter, F., Hermens, W. T., Dijkhuizen, P. A., Claasens, J. W., Eggers, R., van der Sluis, R., Tenenbaum, L., Boer, G. J., & Verhaagen, J. (2004). 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. Experimental Neurology, 189(2), 303-16.
Blits B, et al. 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. Exp Neurol. 2004;189(2):303-16. PubMed PMID: 15380481.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Blits,Bas, AU - Carlstedt,Thomas P, AU - Ruitenberg,Marc Jan, AU - de Winter,Fred, AU - Hermens,Wim T J M C, AU - Dijkhuizen,Paul A, AU - Claasens,Jill W C, AU - Eggers,Ruben, AU - van der Sluis,Ronald, AU - Tenenbaum,Liliane, AU - Boer,Gerard J, AU - Verhaagen,Joost, PY - 2003/09/26/received PY - 2004/04/29/revised PY - 2004/05/11/accepted PY - 2004/9/24/pubmed PY - 2004/10/29/medline PY - 2004/9/24/entrez SP - 303 EP - 16 JF - Experimental neurology JO - Exp. Neurol. VL - 189 IS - 2 N2 - 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. SN - 0014-4886 UR - https://www.unboundmedicine.com/medline/citation/15380481/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014488604001979 DB - PRIME DP - Unbound Medicine ER -