Soluble cell adhesion molecule L1-Fc promotes locomotor recovery in rats after spinal cord injury.
Previous studies suggest that the cell adhesion molecule L1 promotes neurite growth by neutralizing white matter associated inhibitors of axonal growth. We made a soluble chimeric dimer by linking mouse L1 to human Fc. This L1-Fc construct (40 microg/mL) markedly facilitated neurite outgrowth, as well as neuronal adhesion to white matter on frozen sections of spinal cord. We applied L1-Fc intrathecally (200 microg/mL at 0.5 microL/h) to rat spinal cords for 2 weeks after a 25-mm weight drop contusion of the T13 spinal cord. Initial experiments indicated that L1-Fc is present in the spinal cord after 2 weeks of intrathecal infusion and significantly improved locomotor recovery by 6-12 weeks after injury. We then randomized 45 rats to intrathecal infusion of L1-Fc (L1), phosphate-buffered saline controls (PBS), and a mouse monoclonal IgM antibody (M1). By 12 weeks after injury, L1-treated rats recovered significantly (p < 0.005) better locomotor function (BBB score 10.57 +/- 0.25, n = 14) than PBS-treated rats (BBB score 9.00 +/- 0.33, n = 14) or M1-treated (BBB score 8.71 +/- 0.16, n = 14). Only two rats of 22 treated with saline recovered weight-supported ambulation. Of 20 L1-Fc-treated rats, however, 18 recovered weight-supported walking by 12 weeks. The L1-Fc-treated rats also showed more consistent hindlimb contact placing than saline controls. We injected biotinylated dextran amine (BDA) into the motor cortices of 14 rats treated with L1-Fc to label corticospinal axons, comparing these with 13 rats treated with saline. In saline-treated rats, BDA-labeled corticospinal axons often grew up to the impact edge and occasionally into the impact site. L1-treated rats showed longer corticospinal tract growth at the injury site. Three rats had BDA-labeled axons that extended beyond the impact center. One L1-Fc-treated rat showed axonal extension and synapse formation in cord distal to the injury. These results indicate that soluble L1-Fc promotes axonal growth and functional recovery after spinal cord injury. However, the limited corticospinal tract growth across the injury site cannot account for the observed locomotor recovery. Thus, L1 may be stimulating growth of other motor tracts or protecting axons and neurons. More studies are required to elucidate the mechanisms of L1-Fc-induced locomotor recovery.
Department of Neurosurgery, Albert Einstein School of Medicine, New York, NY, USA.
Chanland
C
Roonprapunt
Wencheng
W
Huang
Ray
R
Grill
David
D
Friedlander
Martin
M
Grumet
Suzhen
S
Chen
Melitta
M
Schachner
Wise
W
Young
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D002642:Chick Embryo; D006224:Cricetinae; D005260:Female; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000008:administration & dosage; D007278:Injections, Spinal; D051379:Mice; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology; D039842:Neural Cell Adhesion Molecule L1 / Q000008:administration & dosage* / Q000138:chemical synthesis; D009924:Organ Culture Techniques; D051381:Rats; D020318:Rats, Long-Evans; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D012995:Solubility; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000503:physiopathology; D013904:Thoracic Vertebrae / Q000293:injuries
D007141:Immunoglobulin Fc Fragments; D039842:Neural Cell Adhesion Molecule L1