Focal application of neutralizing antibodies to soluble neurotrophic factors reduces collateral axonal branching after peripheral nerve lesion.
A major reason for the insufficient recovery of function after motor nerve injury are the numerous axonal branches which often re-innervate muscles with completely different functions. We hypothesized that a neutralization of diffusable neurotrophic factors at the lesion site in rats could reduce the branching of transected axons. Following analysis of local protein expression by immunocytochemistry and by in situ hybridization, we transected the facial nerve trunk of adult rats and inserted both ends into a silicon tube containing (i) collagen gel with neutralizing concentrations of antibodies to NGF, BDNF, bFGF, IGF-I, CNTF and GDNF; (ii) five-fold higher concentrations of the antibodies and (iii) combination of antibodies. Two months later, retrograde labelling was used to estimate the portion of motoneurons the axons of which had branched and projected into three major branches of the facial trunk. After control entubulation in collagen gel containing non-immune mouse IgG 85% of all motoneurons projecting along the zygomatic branch sprouted and sent at least one twin axon to the buccal and/or marginal-mandibular branches of the facial nerve. Neutralizing concentrations of anti-NGF, anti-BDNF and anti-IGF-I significantly reduced sprouting. The most pronounced effect was achieved after application of anti-BDNF, which reduced the portion of branched neurons to 18%. All effects after a single application of antibodies were concentration-dependent and superior to those observed after combined treatment. This first report on improved quality of reinnervation by antibody-therapy implies that, in rats, the post-transectional collateral axonal branching can be reduced without obvious harmful effects on neuronal survival and axonal elongation.
Streppel
M
M
Anatomical Institute, University of Cologne, 50931 Cologne, FR Germany.
Azzolin
N
N
Dohm
S
S
Guntinas-Lichius
O
O
Haas
C
C
Grothe
C
C
Wevers
A
A
Neiss
W F
WF
Angelov
D N
DN
D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D019208:Brain-Derived Neurotrophic Factor / Q000037:antagonists & inhibitors / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D005154:Facial Nerve / Q000187:drug effects* / Q000254:growth & development* / Q000276:immunology; D020220:Facial Nerve Injuries / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000276:immunology; D005456:Fluorescent Dyes; D051100:Glial Cell Line-Derived Neurotrophic Factor; D020439:Growth Cones / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000276:immunology; D009414:Nerve Growth Factors / Q000037:antagonists & inhibitors* / Q000276:immunology; D009416:Nerve Regeneration / Q000187:drug effects* / Q000276:immunology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000276:immunology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000276:immunology; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000187:drug effects / Q000276:immunology; D012583:Schwann Cells / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D019208:Brain-Derived Neurotrophic Factor; D005456:Fluorescent Dyes; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D016222:Fibroblast Growth Factor 2; D007334:Insulin-Like Growth Factor I; D020932:Nerve Growth Factor