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.
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.
Blits
Bas
B
Graduate School Neurosciences Amsterdam, Netherlands Institute for Brain Research, 1105 AZ Amsterdam, The Netherlands.
Carlstedt
Thomas P
TP
Ruitenberg
Marc Jan
MJ
de Winter
Fred
F
Hermens
Wim T J M C
WT
Dijkhuizen
Paul A
PA
Claasens
Jill W C
JW
Eggers
Ruben
R
van der Sluis
Ronald
R
Tenenbaum
Liliane
L
Boer
Gerard J
GJ
Verhaagen
Joost
J
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D051100:Glial Cell Line-Derived Neurotrophic Factor; D020439:Growth Cones / Q000378:metabolism / Q000648:ultrastructure; D008159:Lumbar Vertebrae; D008297:Male; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000235:genetics*; D009416:Nerve Regeneration / Q000235:genetics*; D009473:Neuronal Plasticity / Q000235:genetics; D011843:Radiculopathy / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000235:genetics; D012584:Sciatic Nerve / Q000166:cytology / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D013126:Spinal Nerve Roots / Q000293:injuries / Q000473:pathology / Q000601:surgery
D019208:Brain-Derived Neurotrophic Factor; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors