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SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
VOLUME 12 NUMBER 1 • JULY 2015
15
cord injury.
30
Following transplantation a significant attenuation
in mechanical and thermal allodynia with associated pain-induced
behaviour, marked by excessive grooming, was observed and
reduced to pre-injury levels.
In contrast to Braz
et al.’s
study, which only assessed outcome
measures for 28 days post-transplantation, Hendricks
et al.’s
study
observed a sustained anti-nociceptive effect for up to 60 days post-
transplantation with immunohistochemical evidence of sustained
graft viability. Furthermore, in contrast to Braz
et al.’s
study, ES
cell-derived neural and glial grafts exhibited, in addition to anti-
neuropathic effects, significant analgesic effects in a formalin-
induced inflammatory hyperalgesia model suggesting they may be
symptom rather than disease specific.
In a follow-up study Hendricks
et al.’s
group in 2012
anecdotally reported that predifferentiated ES cell grafts rescued
a neuropathic phenotype in a mouse model. The ES cell-derived
grafts exerted neuro-modulatory effects characterised by an
increase in neurotrophic factors and cAMP and decreased levels
of pro-inflammatory cytokines. This contrasts with the functional
integrative mechanism in the Braz
et al
study.
The discrepancies between Braz
et al.’s
study and Hendricks
et al.’s
study may, in part, be explained by the different models
of neuropathic pain used; Braz
et al.
used a peripheral model of
neuropathic pain (sciatic nerve injury) whereas Hendricks
et al.
used
a central model.
A separate study reported that engraftment of predifferentiated
ES cells which tonically secrete serotonin and BDNF into the lumbar
region of rodent models of central neuropathic pain significantly
reduced mechanical allodynia and thermal hyperalgesia for up to
four weeks post-transplantation.
31
The anti-nociceptive effects of
serotonin were augmented by the administration of the serotonin
antagonist methysergide and the serotonin re-uptake inhibitor
fluvoxamine. In contrast to Braz and Hendricks
et al.’s
studies, in this
case the putative anti-nociceptive mechanism was the regeneration
of interrupted descending inhibitory serotonin neuronal inputs.
In summary, the evidence on the utility of ES cells for the
treatment of neuropathic pain is in its infancy. Preclinical research
has focused on the role of ES cells in restoring the inhibitory effects
of GABAergic and serotonergic neurotransmission and, to a lesser
extent, modulation of the hostile pro-inflammatory environment
in central neuropathic pain. The utility of ES cells to regenerate
or modulate other pathophysiological mechanisms of neuropathic
pain such as glutamate release, C-fibre hyperexcitability, altered ion
channel and NMDA receptor expression, and astrocytic and glial
cell activation remains unexplored. Further research is required to
determine the potential utility of ES cells to treat neuropathic pain.
Evidence on the utility of adult stem cells for the
treatment of neuropathic pain
There is a larger evidence base for the efficacy of adult stem cells for
the treatment of neuropathic pain relative to ES cells. Evidence using
an adult NSC line, sourced from the rodent SVZ, showed that NSCs
attenuated neuropathic pain and promoted nerve regeneration in a
rodent chronic constriction injury model.
32
NSCs were administered
via intravenous injection and preferentially homed towards the
ipsilaterally lesioned nerve; evidence suggests this pattern of
homing may be related to myelin modifications induced by nerve
injury.
33
Analgesic effects measured by a reduction in mechanical
allodynia and thermal hyperalgesia were observed within three days
following NSC administration, which correlated with histological
evidence of NSC presence at the nerve injury site. The persistence of
the analgesic effect between seven and 14 days following grafting
correlated with perilesional migration of a high density of fibroblasts,
Schwann cells and macrophages, which facilitated regeneration,
neurite outgrowth, sprouting, and an improvement in nerve
morphology. Evidence suggests this is due to grafted NSCs exhibiting
trophic and reparative effects.
34
In support of this, the correlation
between NSC administration and anti-nociceptive effects were
associated with: a rapid decrease in Fos expression in laminae I–VI
(high levels are normally associated with neuronal activity following
noxious stimulation);
35
a decrease in immunoreactivity for substance
P in the same region (substance P has been associated with increased
neuropathic pain in rodents);
36
and a reduction in mRNA levels of the
pro-inflammatory pro-algesic cytokines IL-1 and IL-6, coupled with a
rise in mRNA levels of the anti-inflammatory cytokine IL-10. These
findings suggest that NSCs act as local modifying agents transforming
the hostile pro-inflammatory neurochemical environment associated
with nerve injury into a more permissive milieu. This facilitates nerve
regeneration and analgesia. However, the pro-inflammatory micro-
environment may not be entirely harmful to regeneration (see later).
The strength of Franchi
et al.’s
study is based on new first
evidence that intravenous administration of NSCs has bidirectional
effects on the immune response – decreasing the injurious pro-
inflammatory cytokine cascade and activating the neuroprotective
anti-inflammatory cytokine response. Interestingly, the analgesic
effect of NSCs preceded the morphological signs of nerve repair
and was sustained after NSCs disappeared from the lesion site.
Franchi
et al.’s
findings are corroborated by a study that found
MSCs transplanted into neuronal tissue ameliorated peripheral
neuropathic pain.
37
Similar to the immunomodulatory mechanisms
from Franchi
et al.’s
study, in this case the recorded anti-nociceptive
effects were secondary to the prevention of injury-induced changes
in galanin, neuropeptide Y, and neuropeptide Y Y1-receptor
expression in a single ligature nerve constriction rodent model.
This may be explained by the bi-directional effects of galanin
on neuropathic pain. Galanin is upregulated following nerve injury;
however, the functional significance of this is dependent on the
type and location of the GAL receptor stimulated. This may result
in either: pro-nociceptive effects via activation of pre-synaptic
GAL2 receptors on primary afferents; or anti-nociceptive effects
via stimulation of GAL1 receptors on dorsal horn neurones.
38
In
Coronel
et al.’s
study it is likely that the grafted MSCs exerted
anti-nociceptive effects by either preventing injury-induced galanin
upregulation with stimulation of pre-synaptic GAL2 receptors on
primary afferents, or alternatively, stimulating GAL1 receptors. Other
evidence supportive of the reparative immunological mechanisms in
Franchi
et al.’s
study have shown that: the efficacy of transplanted
NSCs in the treatment of neuropathic pain is mediated via
neuroprotective and immunomodulatory mechanisms;
39
and that
in a mouse model of spared nerve injury, intra-ventricular injection
of human MSCs decreased mRNA levels of the pro-inflammatory
IL-1 gene and suppressed activation of astrocytes and microglia,
which was associated with a reduction in pain-like behaviours.
40
The utility of intravenous systemic NSC administration in the
treatment of neuropathic pain is further corroborated by evidence
on the physiological mechanisms underlying NSCmigration, namely,
that NSCs cross the blood–brain barrier and enter the CNS where
they modulate pain.
41
Leading on from this, the intravenous route
of NSC administration has a more transferable putative clinical