Stimulation of axonal sprouting by trophic factors immobilized within the wound core.
Traumatic injury to the CNS results in peri-wound sprouting without significant axonal growth beyond the lesion edge. We have previously demonstrated that dopaminergic sprouting in the injured striatum follows an increasing gradient of BDNF and GDNF expression, with sprouting ceasing at the point of maximal factor expression. Progressively more complicated associations of sprouting fibers with increasingly activated microglia and macrophages suggest these factors are localized to the cell surface. To establish whether an increased concentration of immobilized BDNF and GDNF could stimulate axonal growth beyond the lesion edge, both factors were covalently attached to 10 microm polycarbonate microspheres. These spheres were implanted into the site of striatal injury 1 week after lesioning. A profusion of axons grew from the region of the lesion edge across the surface of the spheres. Some axons traversed the entire site of injury. Ultrastructural examination demonstrated the juxtaposition of regenerating axons to the surface of implanted spheres. CSPG immunostaining demonstrated that, in animals implanted with neurotrophin-microspheres, axonal growth was induced beyond the area of maximal CSPG reactivity. Surprisingly however, CSPG production at the wound edge was greater in control animals than those implanted with neurotrophin-microspheres. Overall, we show that axonal growth can be encouraged beyond the wound edge by an elevated concentration of immobilized trophic factors. This growth occurs despite the presence of inhibitory CSPGs at the lesion edge. Axonal growth appears to be stimulated mainly via the direct effects of neurotrophins. However, there also appears to be an indirect mechanism whereby neurotrophins reduce the synthesis of CSPG at the wound edge, making the peri-wound environment more permissive.
Batchelor
Peter Egerton
PE
Departments of Medicine and Neurology, University of Melbourne, Austin Health, Heidelberg Victoria 3084, Australia.
Wills
Taryn Elizabeth
TE
Hewa
Ajith Pedru
AP
Porritt
Michelle Julie
MJ
Howells
David William
DW
D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001930:Brain Injuries / Q000188:drug therapy* / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology / Q000627:therapeutic use; D011508:Chondroitin Sulfate Proteoglycans / Q000032:analysis / Q000378:metabolism; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000032:analysis / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology / Q000627:therapeutic use; D020439:Growth Cones / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008863:Microspheres; D009414:Nerve Growth Factors / Q000494:pharmacology* / Q000627:therapeutic use; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D011108:Polymers / Q000737:chemistry; D016896:Treatment Outcome; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology
D015415:Biomarkers; D019208:Brain-Derived Neurotrophic Factor; D011508:Chondroitin Sulfate Proteoglycans; D050483:Dopamine Plasma Membrane Transport Proteins; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D011108:Polymers; C017902:lexan