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when inflammation and axonal injury were established already,
suggesting that it might also actively stimulate repair.
PLP-induced relapsing-remitting EAE in SJL mice resembles
relapsing-remitting MS, the most common form of MS. It is char-
acterized by an onset around day 11-14, in which the mice develop
the first wave of paralysis, after which they recover, going towards
a remitting phase, but then one or more relapses may occur.
Mononuclear cell infiltrates and extensive primary demyelination
and remyelination account for relapses and remissions. Therapeutic
EPO (5,000 IU/kg) administered for 7 days starting from disease
onset reduced clinical score, inflammation and demyelination.
Importantly, it also increased oligodendrocyte progenitor cell pro-
liferation and BDNF positive cell density, indicating also in this
model induction of an active repair process (
16
).
Interestingly, in both MOG-induced chronic progressive and
PLP-induced relapsing-remitting models of EAE, we found an
increased stable expression of endogenous EPO in the spinal cord
(
17
). In a subsequent study Kang et al. also found elevated levels
of EPO in spinal cord of rats with MBP-induced acute EAE at the
peak of the disease, thus confirming our observation (
18
). It is
therefore likely that EPO is part of an endogenous mechanism of
repair induced by the disease itself.
It should be noted that EPO is safe when administered to ane-
mic patients, but when administered to non anemic patients has
side effects, and it may be prothrombotic due to its erythropoietic
activity (
19
). This may be a problem when treating patients with
chronic diseases, like MS, who may obviously need long treat-
ments. Interestingly, Leist et al. found that carbamylated EPO
(CEPO), a derivative of EPO in which all lysines are transformed
to homocitrulline by carbamylation, modification already known
to abolish EPO's erythropoietic activity, retained EPO's neuropro-
tective activity and also protected mice with MOG-induced EAE
(
20
). In this study, CEPO was administered at day 3 after MOG
immunization, according to the preventive schedule, and at week
10, according to the late therapeutic schedule. The fact that CEPO
protected the mice also when administered at week 10, after 4
weeks of stable chronic disease, reinforces previous observations
suggesting that EPO and derivatives may act not only inhibiting
inflammation but also at some level as neuroregenerative agents.
In a systematic study in the same model of MOG-induced
chronic progressive EAE in C57BL/6 mice, in which EPO and
CEPO were administered in parallel at different doses according to
preventive, therapeutic, or late therapeutic schedules, both EPO and
CEPO were found to reduce clinical symptoms and inhibit
inflammatory cytokines in spinal cord and peripheral lymphocytes
(
21
). Although the preventive schedule was obviously more
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