Delayed Nogo receptor therapy improves recovery from spinal cord contusion.
OBJECTIVE
Myelin-associated inhibitors play a role in limiting axonal growth in the adult central nervous system. Blocking these inhibitors may promote neurological recovery from spinal cord contusion.


METHODS
The soluble Nogo-66 receptor (NgR(310)ecto-Fc) protein, which can neutralize three myelin inhibitors, was infused into rats after spinal cord contusion for 28 days. Treatment was initiated intrathecally at the time of injury or 3 days after injury by the intracerebroventricular route at a dose of 0.29 mg/kg/day. Recovery of locomotion and of axonal growth was assessed. Some animals received combination therapy with NgR(310)ecto-Fc plus rolipram, a cyclic adenosine monophosphate phosphodiesterase inhibitor.


RESULTS
Seven weeks after spinal injury, the Basso-Beattie Bresnahan locomotor scores were significantly improved in the 3-day delayed NgR(310)ecto-Fc treatment group (9.5 +/- 0.7; n = 16) versus the vehicle-treated group, (6.75 +/- 0.7; n = 15) (p < or = 0.01, analysis of variance). The percentage of NgR(310)ecto-Fc-treated animals able to support their weight was twice that in the control group. Delayed therapy was as efficacious as acute therapy. Addition of rolipram did not alter recovery. The beneficial behavioral effects of NgR(310)ecto-Fc correlated with sprouting of raphespinal axons in the caudal spinal cord and of corticospinal axons in the rostral spinal cord.


CONCLUSIONS
NgR(310)ecto-Fc treatment improves outcome in a rodent model that closely mimicked human spinal cord injury.
Wang
Xingxing
X
Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT.
Baughman
Kenneth W
KW
Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT.
Basso
D Michele
DM
Division of Physical Therapy, Ohio State University, Columbus, OH.
Strittmatter
Stephen M
SM
Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT.
D000818:Animals; D001369:Axons / Q000187:drug effects; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D007276:Injections, Intraventricular; D008124:Locomotion / Q000187:drug effects; D009186:Myelin Sheath / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use; D011712:Pyramidal Tracts / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D020127:Recovery of Function; D020889:Rolipram / Q000627:therapeutic use; D013119:Spinal Cord Injuries / Q000628:therapy*; D013997:Time Factors; D016896:Treatment Outcome
C495858:NgR(310) Ecto-Fc protein; D010726:Phosphodiesterase Inhibitors; D011993:Recombinant Fusion Proteins; D020889:Rolipram