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stimulation but also demonstrates that, after reinnervation occurred, no overall
functional benefit occurs from the treatment (
Gordon, Amirjani, Edwards, &
Chan, 2010; Hamilton et al., 2011
). However, shortening of regeneration
times is of high value for patients suffering from peripheral nerve lesions.
3.2. Impact of electrical stimulation on expression of
neurotrophic factors
It is well demonstrated that short-term low-frequency electrical stimulation
proximal to the suture site of freshly transected and readapted nerves
increases the expression of BDNF and its specific receptor trkB in
axotomized motoneurons (
Al-Majed, Brushart, & Gordon, 2000
). The
upregulation of both BDNF and trkB is crucially involved in the
upregulation of regeneration-associated genes such as T
a
1-tubulin and
growth-associated protein 43 (GAP-43) as well as the subsequent faster axo-
nal elongation (
Al-Majed, Tam, & Gordon, 2004; Gordon, Sulaiman, &
Ladak, 2009
).
With sophisticated studies, it has been proven that (i) the upregulation of
neurotrophic factors is essential to mediate the cellular mechanisms of accel-
erated axonal elongation and target reinnervation after electrical stimulation
(
Gordon, 2010
) and that (ii) the cellular mechanism is mainly based on the
activation of trkB signaling with ligands produced either by Schwann cells or
the regenerating axons themselves (
English, Schwartz, Meador, Sabatier, &
Mulligan, 2007
).
It has been discovered that prior to the upregulation of BDNF and the
trkB receptor, electrical stimulation induces an increased influx of calcium
into the neurons (
Gordon, 2009; Wenjin et al., 2011
). The calcium influx
induces phosphorylation of the Ca
2
รพ
-activated extracellular signal regulated
kinase, Erk, which is another prerequisite for the elevated BDNF expression
after electrical stimulation (
Wenjin et al., 2011
). Furthermore, the described
calcium influx is followed by an increase of intracellular cAMP levels, and
downstream of cAMP, protein kinase A promotes expression of
the
regeneration-associated genes for axonal elongation (
Gordon, 2009
).
In our own investigation of the effect of electrical stimulation after long
(13 mm)-gap nerve tube repair, no relative upregulation of BDNF-mRNA
levels related to electrical stimulation in sensory or motoneurons was seen
but a prolonged BDNF expression which was accompanied by a significant
upregulation of GAP-43 mRNA levels within the lumbar spinal cord
2 weeks after surgery and stimulation (
Haastert-Talini et al., 2011
).
