Synergistic effect of basic fibroblast growth factor and methylprednisolone on neurological function after experimental spinal cord injury.
The authors evaluated the effects of exogenous basic fibroblast growth factor (bFGF) in combination with intravenous methylprednisolone on neurological function and cord angiogenesis in a model of spinal cord injury. Cord injury was produced by extradural clip compression through a T-1 laminectomy. Rats were randomized to one of six groups. Group A was given sham laminectomy without cord injury or treatment. The remaining animals were divided into five groups: untreated injury (Group B); injury treated with methylprednisolone (Group C); combined methylprednisolone and 1 microgram bFGF administered locally at the site of injury (Group D); methylprednisolone and 3 micrograms bFGF (Group E); or methylprednisolone and 3 micrograms heated bFGF (Group F). Groups C through F received treatment 1 hour after cord injury. At 1, 2, 3, and 4 weeks after surgery, neurological function of hindlimbs was assessed by blinded observers using an established multiple test method (toe spread, reflexes to extension, pain, and pressure as well as inclined plane and swim test) with tests graded and results expressed as a combined behavioral score. Animals were killed to study spinal cord angiogenesis in cord samples (2-mm sections proximal and distal to the injury site) by capillary density determination. Behavioral scores over time showed a significant difference among Groups B, C, D, E, and F (p = 0.0044), with Groups E and B maintaining highest and lowest scores, respectively. There was a linear dose effect of bFGF over time (p = 0.0187). At 4 weeks, scores showed a difference among the five groups (p = 0.006), with Group E showing higher scores than any other treatment group (for example, vs. group F: p = 0.035). There was a significant difference among the groups in gray matter capillary density counts: proximal (p = 0.0192) and distal (p = 0.024), whereas white matter capillary counts were similar across treatment groups. These results show: 1) possible synergism exists between methylprednisolone and bFGF, such that combinations of these drugs significantly enhance neurological recovery, 2) bFGF exhibits a dose-response effect in function but not in capillary density, and 3) heated, inactivated bFGF is not therapeutically effective.
Baffour
R
R
Department of Surgery, Baystate Medical Center, Springfield, Massachusetts, USA.
Achanta
K
K
Kaufman
J
J
Berman
J
J
Garb
J L
JL
Rhee
S
S
Friedmann
P
P
D000704:Analysis of Variance; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D005346:Fibroblast Growth Factors / Q000494:pharmacology* / Q000627:therapeutic use; D006614:Hindlimb / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology / Q000627:therapeutic use*; D009068:Movement / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000503:physiopathology; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013116:Spinal Cord / Q000098:blood supply / Q000187:drug effects*; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000503:physiopathology
D005346:Fibroblast Growth Factors; D008775:Methylprednisolone