PDE4 and BDNF overlap in peripheral nerve repair
Kofi
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The role of neurotrophic factors in nerve regeneration.
Gordon T.
Centre for Neuroscience, Division of Physical Medicine and
Rehabilitation, Faculty of Medicine and Dentistry, University of
Alberta, Edmonton, Alberta, Canada.
This review considers the 2 sources of neurotrophic factors in the
peripheral nervous system (PNS), the neurons and the nonneuronal cells
in the denervated distal nerve stumps, and their role in axon
regeneration. Morphological assessment of regenerative success in
response to administration of exogenous growth factors after nerve
injury and repair has indicated a role of the endogenous neurotrophic
factors from Schwann cells in the distal nerve stump. However, the
increased number of axons may reflect more neurons regenerating their
axons and/or increased numbers of axon sprouts from the same number of
neurons. Using fluorescent dyes to count neurons that regenerated their
axons across a suture site and into distal nerve stumps, brain-derived
neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor
(GDNF) were found not to increase the number of neurons that regenerated
their axons after immediate nerve repair. Nevertheless, the factors did
reverse the deleterious effect of delayed nerve repair, indicating that
the axons that regenerate into the distal nerve stump normally have
access to sufficient levels of endogenous neurotrophic factors to
sustain their regeneration, while neurons that do not have access to
these factors require exogenous factors to sustain axon regeneration.
Neurons upregulate neurotrophic factors after axotomy. The upregulation
is normally slow, beginning after 7 days and occurring in association
with a protracted period of axonal regeneration in which axons grow out
from the proximal nerve stump across a suture site over a period of 1
month in rodents. This staggered axon regeneration across the suture
site is accelerated by a 1-hour period of low-frequency electrical
stimulation that simultaneously accelerates the expression of BDNF and
its trkB receptor in the neurons. Elevation of the level of BDNF after 2
days to > 3 times that found in unstimulated neurons was accompanied by
elevation of the level of cAMP and followed by accelerated upregulation
of growth-associated genes, tubulin, actin, and GAP-43 and
downregulation of neurofilament protein. Elevation of cAMP levels via
rolipram inhibition of phosphodiesterase 4 mimicked the effect of the
low-frequency electrical stimulation. In conclusion, the enhanced
upregulation of neurotrophic factors in the electrically stimulated
axotomized neurons accelerates axon outgrowth into the distal nerve
stumps where endogenous sources of growth factors in the Schwann cells
support the regeneration of the axons toward the denervated targets. The
findings provide strong support for endogenous neurotrophic factors of
axotomized neurons and of denervated Schwann cells playing a critical
role in supporting axon regeneration in the PNS.
PMID: 19228105