Biology Reference
In-Depth Information
efficacious, both EPO and CEPO worked at comparable level even
when administered according to a therapeutic schedule at the low-
est dosage tested (0.5
g/kg, three times a week). Also asialoEPO,
that since desialylated has a very short half-life and therefore is not
erythropoietic, ameliorated the clinical score of the disease.
However, in this study it was administered at the highest dose
according to the preventive schedule, and therefore, more studies
would be needed to compare its efficacy to that of EPO or CEPO.
More recently, Yuan et al. have showed that EPO acts also as
an immunomodulator in MOG-induced EAE in C57BL/6 mice.
In this study, EPO (5,000 IU/kg) was administered 3 days after
immunization, according to a preventive schedule, or 7 days
after immunization, still before onset, and was shown to reduce
disease severity and to have immunomodulatory effects in the
periphery and spinal cord, inhibiting the proliferation of patho-
genic T-cells and favoring the expansion of protective T-cell sub-
sets (
22
). Using a very similar treatment schedule (5,000 IU,
preventive), Chen et al. confirmed EPO immunomodulatory
effects on pathogenic and protective T-cell subsets, and also
found increased expression of heme oxygenase-1 (HO-1), an
enzyme with antioxidant potential, in central nervous system
and spleen of mice with MOG-induced EAE (
23
).
In the same model darbepoetin alfa, a hyperglycosylated EPO
mutant, administered on day 13 and 17 after MOG immunization
(2.5
μ
g/kg, i.p., therapeutic schedule) reduced clinical symptoms,
apparently through induction of tissue inhibitor of metalloprotease
(TIMP-1), since it increased the number of astrocytes expressing
TIMP-1 in brain and spinal cord and did not have any protective
effect in Timp-1 null mice. Of note, at this dose darbepoetin alfa
did not increase the hematocrit (
24
).
Importantly, these results have been translated to the clinic in
a small proof of concept clinical trial in patients with chronic pro-
gressive MS, in which treatment with a high dose of EPO improved
motor and cognitive functions. The efficacy of EPO in MS patients
has been reviewed by Erenreich (
4
). Although more data corrobo-
rate EPO's anti-inflammatory activity, preclinical data obtained in
EAE models suggesting that EPO also inhibits axonal damage and
induces oligodendrogenesis and repair have been confirmed in this
pilot clinical trial, in which it has been clearly shown that EPO can
improve cognitive functions.
More studies are needed to elucidate the mechanism by which
EPO may have neuroprotective and neurogenerative effects in
EAE and MS, focusing on neurogenic/neurotrophic effects and
induction of remyelination. Importantly, studies with asialoEPO
and CEPO have shown that derivatives of EPO devoid of erythro-
poietic activity have therapeutic efficacy in EAE.
μ
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