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due to the tissue protective effects of EPO, resulting in increased
survival of neuronal cells and reduced inflammation of the nervous
system. In 2003, Campana and Meyers showed that treating rats
with rhEpo following L5 spinal nerve crush (SNC) alleviated allo-
dynia and decreased the time to recover from SNC, whereas ani-
mals in the vehicle treatment group showed a higher degree of
allodynia and a longer time to reach recovery. This effect was sup-
ported by the observation that rhEPO prevented apoptosis of dor-
sal root ganglion (DRG) cells and induction of phosphorylated
Jak-2, a molecule when phosphorylated induces apoptosis (
7
). In
addition to the peripheral effects observed, EPO showed a central
effect by protecting neurons in the spinal cord in a rat model of
neuropathic pain. Following L5 proximal nerve root crush, rhEPO
treated animals showed less allodynia when compared to vehicle
treated animals which was accompanied by less apoptosis of neu-
rons in both the ventral and dorsal horns of the spinal cord and
identification of the EPO receptor (EPOR) and lower levels of
TNF-
in spinal cord neurons (
8
). A study performed by Keswani
et al. (
9
) assessed the role of the EPOR and showed neuroprotec-
tive effects in both in vitro and in vivo models. They showed
in vitro that EPO is being produced by neurons and Schwann cells
and that the EPOR is being expressed predominantly by neurons
and was not restricted to the soma of the neuron. Additionally they
showed beneficial effects of EPO in neurotoxicity. In an animal
model of nerve damage they showed that EPO mRNA was
increased in dorsal root ganglia (DRG) as well as in the sciatic
nerve, while the EPOR mRNA was increased solely in the DRG.
Additionally, in acrylamide induced neuropathy, EPO protected
denervation of the skin, improved motor function in the grip
strength test and prevented hyperalgesia in the paw withdrawal
test. The role of EPO and TNF-
α
in neuropathic pain states was
again explored by Campana et al. (
10
) in a chronic constriction
injury model (CCI). They showed that rhEPO was able to reduce
pain behavior in animals with nerve injury and that TNF-
α
was
increased in injured nerves proximal to the injury. The induction
of TNF-
α
was counteracted by rhEPO resulting in lower levels of
the cytokine. Additionally, Jia et al. (
11
) showed that treating ani-
mals that had received an L5 spinal nerve transection with rhEPO
showed decreased mechanical and thermal hyperalgesia with
respect to control animals. This coincided with less microglia acti-
vation, decreased pro-inflammatory cytokine production (IL-1, 6
and TNF-
α
), increased anti-inflammatory cytokine production
(IL-10) and decreased the expression of NF-
α
B, a signaling mole-
cule important in pain processing. Both the expression of the
cytokines and NF-
κ
B was shown to be dose dependent (
12
). Also
EPO derivatives devoid of erythropoietic properties show these
effects. In a model of neuropathic pain where nucleus pulposus
was applied to the DRG of animals EPO and asialo-EPO, an EPO
κ
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