Nogo-66 receptor antagonist peptide (NEP1-40) administration promotes functional recovery and axonal growth after lateral funiculus injury in the adult rat.
OBJECTIVE
The myelin protein Nogo inhibits axon regeneration by binding to its receptor (NgR) on axons. Intrathecal delivery of an NgR antagonist (NEP1-40) promotes growth of injured corticospinal axons and recovery of motor function following a dorsal hemisection. The authors used a similar design to examine recovery and repair after a lesion that interrupts the rubrospinal tract (RST).


METHODS
Rats received a lateral funiculotomy at C4 and NEP1-40 or vehicle was delivered to the cervical spinal cord for 4 weeks. Outcome measures included motor and sensory tests and immunohistochemistry.


RESULTS
Gait analysis showed recovery in the NEP1-40-treated group compared to operated controls, and a test of forelimb usage also showed a beneficial effect. The density of labeled RST axons increased ipsilaterally in the NEP1-40 group in the lateral funiculus rostral to the lesion and contralaterally in both gray and white matter. Thus, rubrospinal axons exhibited diminished dieback and/or growth up to the lesion site. This was accompanied by greater density of 5HT and calcitonin gene-related peptide axons adjacent to and into the lesion/matrix site in the NEP1-40 group.


CONCLUSIONS
NgR blockade after RST injury is associated with axonal growth and/or diminished dieback of severed RST axons up to but not into or beyond the lesion/matrix site, and growth of serotonergic and dorsal root axons adjacent to and into the lesion/matrix site. NgR blockade also supported partial recovery of function. The authors' results indicate that severed rubrospinal axons respond to NEP1-40 treatment but less robustly than corticospinal, raphe-spinal, or dorsal root axons.
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA. yc94@drexel.edu
Y
Y
Cao
J S
JS
Shumsky
M A
MA
Sabol
R A
RA
Kushner
S
S
Strittmatter
F P T
FP
Hamers
D H S
DH
Lee
S A
SA
Rabacchi
M
M
Murray
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D003714:Denervation; D004525:Efferent Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D058851:GPI-Linked Proteins; D020439:Growth Cones / Q000187:drug effects* / Q000378:metabolism; D009185:Myelin Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D000070816:Nogo Receptor 1; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D011712:Pyramidal Tracts / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D012012:Red Nucleus / Q000187:drug effects / Q000378:metabolism; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D013126:Spinal Nerve Roots / Q000187:drug effects / Q000378:metabolism; D016896:Treatment Outcome; D014855:Wallerian Degeneration / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology
D058851:GPI-Linked Proteins; D009185:Myelin Proteins; C509624:NEP1-40 protein, human; D000070816:Nogo Receptor 1; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; C486581:Rtn4r protein, rat