title: BDNF and NT-4/5 prevent atrophy of rat rubrospinal neurons after cervical axotomy, stimulate GAP-43 and Talpha1-tubulin mRNA expression, and promote axonal regeneration.
abstract: Rubrospinal neurons (RSNs) undergo a marked atrophy in the second week after cervical axotomy. This delayed atrophy is accompanied by a decline in the expression of regeneration-associated genes such as GAP-43 and Talpha1-tubulin, which are initially elevated after injury. These responses may reflect a deficiency in the trophic support of axotomized RSNs. To test this hypothesis, we first analyzed the expression of mRNAs encoding the trk family of neurotrophin receptors. In situ hybridization revealed expression of full-length trkB receptors in virtually all RSNs, which declined 7 d after axotomy. Full-length trkC mRNA was expressed at low levels. Using RT-PCR, we found that mRNAs encoding trkC isoforms with kinase domain inserts were present at levels comparable to that for the unmodified receptor. TrkA mRNA expression was not detected in RSNs, and the expression of p75 was restricted to a small subpopulation of axotomized cells. In agreement with the pattern of trk receptor expression, infusion of recombinant human BDNF or NT-4/5 into the vicinity of the axotomized RSNs, between days 7 and 14 after axotomy, fully prevented their atrophy. This effect was still evident 2 weeks after the termination of BDNF treatment. Moreover, BDNF or NT-4/5 treatment stimulated the expression of GAP-43 and Talpha1-tubulin mRNA and maintained the level of trkB expression. Vehicle, NGF, or NT-3 treatment had no significant effect on cell size or GAP-43 and Talpha1-tubulin expression. In a separate experiment, infusion of BDNF also was found to increase the number of axotomized RSNs that regenerated into a peripheral nerve graft. Thus, in BDNF-treated animals, the prevention of neuronal atrophy and the stimulation GAP-43 and Talpha1-tubulin expression is correlated with an increased regenerative capacity of axotomized RSNs.
authors.affiliation: Department of Physiology, University of Ottawa, Ontario, Canada KIH 8M5.
authors.forename: N R
authors.initials: NR
authors.lastname: Kobayashi
authors.forename: D P
authors.initials: DP
authors.lastname: Fan
authors.forename: K M
authors.initials: KM
authors.lastname: Giehl
authors.forename: A M
authors.initials: AM
authors.lastname: Bedard
authors.forename: S J
authors.initials: SJ
authors.lastname: Wiegand
authors.forename: W
authors.initials: W
authors.lastname: Tetzlaff
mesh_terms: D000818:Animals; D001284:Atrophy; D001369:Axons / Q000187:drug effects / Q000502:physiology; D019771:Axotomy; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D019922:GAP-43 Protein / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009416:Nerve Regeneration / Q000187:drug effects*; D009474:Neurons / Q000737:chemistry / Q000187:drug effects / Q000648:ultrastructure; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020933:Neurotrophin 3; D011518:Proto-Oncogene Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D020801:Receptor, Ciliary Neurotrophic Factor; D020917:Receptor, trkA; D020812:Receptor, trkC; D017475:Receptors, Nerve Growth Factor / Q000235:genetics; D012012:Red Nucleus / Q000166:cytology; D012584:Sciatic Nerve / Q000637:transplantation; D013116:Spinal Cord / Q000166:cytology / Q000473:pathology / Q000601:surgery; D013119:Spinal Cord Injuries / Q000503:physiopathology; D014404:Tubulin / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D019922:GAP-43 Protein; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D020933:Neurotrophin 3; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; D014404:Tubulin; C071951:neurotrophin 5; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D020812:Receptor, trkC; C073922:neurotrophin 4