title: A dose-dependent facilitation and inhibition of peripheral nerve regeneration by brain-derived neurotrophic factor.
abstract: The time-dependent decline in the ability of motoneurons to regenerate their axons after axotomy is one of the principle contributing factors to poor functional recovery after peripheral nerve injury. A decline in neurotrophic support may be partially responsible for this effect. The up-regulation of BDNF after injury, both in denervated Schwann cells and in axotomized motoneurons, suggests its importance in motor axonal regeneration. In adult female Sprague-Dawley rats, we counted the number of freshly injured or chronically axotomized tibial motoneurons that had regenerated their axons 1 month after surgical suture to a freshly denervated common peroneal distal nerve stump. Motor axonal regeneration was evaluated by applying fluorescent retrograde neurotracers to the common peroneal nerve 20 mm distal to the injury site and counting the number of fluorescently labelled motoneurons in the T11-L1 region of the spinal cord. We report that low doses of BDNF (0.5-2 microg/day for 28 days) had no detectable effect on axonal regeneration after immediate nerve repair, but promoted axonal regeneration of motoneurons whose regenerative capacity was reduced by chronic axotomy 2 months prior to nerve resuture, completely reversing the negative effects of delayed nerve repair. In contrast, high doses of BDNF (12-20 microg/day for 28 days) significantly inhibited motor axonal regeneration, after both immediate nerve repair and nerve repair after chronic axotomy. The inhibitory actions of high dose BDNF could be reversed by functional blockade of p75 receptors, thus implicating these receptors as mediators of the inhibitory effects of high dose exogenous BDNF.
authors.affiliation: University Centre for Neuroscience, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada T6G 2S2.
authors.forename: J G
authors.initials: JG
authors.lastname: Boyd
authors.forename: T
authors.initials: T
authors.lastname: Gordon
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000494:pharmacology*; D048429:Cell Size / Q000187:drug effects / Q000502:physiology; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000009:adverse effects; D005260:Female; D005456:Fluorescent Dyes; D009046:Motor Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009416:Nerve Regeneration / Q000187:drug effects* / Q000502:physiology; D059348:Peripheral Nerve Injuries; D010525:Peripheral Nerves / Q000187:drug effects* / Q000601:surgery; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D005456:Fluorescent Dyes; D020800:Receptor, Nerve Growth Factor