Effect of combined treatment with methylprednisolone and soluble Nogo-66 receptor after rat spinal cord injury.
Methylprednisolone (MP) is a synthetic glucocorticoid used for the treatment of spinal cord injury (SCI). Soluble Nogo-66 receptor (NgR) ectodomain is a novel experimental therapy for SCI that promotes axonal regeneration by blocking the growth inhibitory effects of myelin constituents in the adult central nervous system. To evaluate the potential complementarity of these mechanistically distinct pharmacological reagents we compared their effects alone and in combination after thoracic (T7) dorsal hemisection in the rat. Treatment with an ecto-domain of the rat NgR (27-310) fused to a rat IgG [NgR(310)ecto-Fc] (50 microm intrathecal, 0.25 microL/h for 28 days) or MP alone (30 mg/kg i.v., 0, 4 and 8 h postinjury) improved the rate and extent of functional recovery measured using Basso, Beattie, Bresnahan (BBB) scoring and footprint analysis. The effect of MP treatment on BBB score was apparent the day after SCI whereas the effect of NgR(310)ecto-Fc was not apparent until 2 weeks after SCI. NgR(310)ecto-Fc or MP treatment resulted in increased axonal sprouting and/or regeneration, quantified by counting biotin dextran amine-labeled corticospinal tract axons, and increased the number of axons contacting motor neurons in the ventral horn gray matter caudal to the lesion. Combined treatment with NgR(310)ecto-Fc and MP had a more pronounced effect on recovery of function and axonal growth compared with either treatment alone. The data demonstrate that NgR(310)ecto-Fc and MP act in a temporally and mechanistically distinct manner and suggest that they may have complementary effects.
Ji
Benxiu
B
Department of Pharmacology, Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA.
Li
Mingwei
M
Budel
Stephane
S
Pepinsky
R Blake
RB
Walus
Lee
L
Engber
Thomas M
TM
Strittmatter
Stephen M
SM
Relton
Jane K
JK
D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D001522:Behavior, Animal; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism; D002478:Cells, Cultured; D002642:Chick Embryo; D003911:Dextrans / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D058851:GPI-Linked Proteins; D005727:Ganglia, Spinal / Q000166:cytology; D007074:Immunoglobulin G / Q000627:therapeutic use; D007796:Laminectomy / Q000379:methods; D008775:Methylprednisolone / Q000627:therapeutic use*; D009185:Myelin Proteins; D009186:Myelin Sheath / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D000070816:Nogo Receptor 1; D011712:Pyramidal Tracts / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide / Q000096:biosynthesis / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D020127:Recovery of Function / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000503:physiopathology
D003911:Dextrans; D058851:GPI-Linked Proteins; D007074:Immunoglobulin G; D009185:Myelin Proteins; D000070816:Nogo Receptor 1; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; D011994:Recombinant Proteins; C486581:Rtn4r protein, rat; C076397:biotinylated dextran amine; D001710:Biotin; D008775:Methylprednisolone