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Volume 17, Number 24,
Issue of December 15, 1997
pp. 9583-9595
BDNF and NT-4/5 Prevent Atrophy of Rat Rubrospinal Neurons after
Cervical Axotomy, Stimulate GAP-43 and T 1-Tubulin mRNA Expression,
and Promote Axonal Regeneration
Received April 24, 1997; revised Sept. 17, 1997; accepted Sept. 25, 1997.
Nao R. Kobayashi1, 2,
Da-Peng Fan2,
Klaus M. Giehl1,
Annie M. Bedard1,
Stanley J. Wiegand3, and
Wolfram Tetzlaff1, 2
1 Department of Physiology, University of Ottawa,
Ontario, Canada KIH 8M5, 2 Departments of Zoology and
Surgery, University of British Columbia, Vancouver, British Columbia,
Canada V6T 1Z4, and 3 Regeneron Pharmaceuticals
Inc., Tarrytown, New York 10591-6707
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 T 1-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 T1-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
T1-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 T1-tubulin expression is correlated with an increased
regenerative capacity of axotomized RSNs.
Key words:
axotomy;
spinal cord injury;
neurotrophin;
regeneration,
red nucleus;
gene expression;
neuronal atrophy;
cell body response;
peripheral nerve transplant
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