Biology Reference
In-Depth Information
1.1 Ef fi cacy of
EPO in Several Models
of EAE
In the first study in Lewis rats with myelin basic protein (MBP)-induced
EAE, EPO delayed disease onset and decreased clinical symptoms
(
3
). In a later study in the same model, EPO was shown to inhibit
the production of inflammatory cytokines, in particular TNF and
IL6, in spinal cord and brain (
7
).
MBP-induced EAE in Lewis rat is a monophasic disease with
onset around 10 days after immunization, after which the animals
recover completely, and it is characterized by a strong inflammatory
component but limited demyelination, that is the primary feature of
MS. EPO (50
g/kg) was administered daily, intraperitoneally (i.p.),
starting 3 days after immunization, well before the onset of the dis-
ease. It was clear from these studies that EPO inhibited inflammation,
but not if it could also target the neurodegenerative aspect of EAE.
In a model of MOG-induced EAE in Brown Normay rats,
characterized by optic neuritis with early axonal damage of the
optic nerve, similar to the one observed in MS patients, EPO
treatment (50
μ
g/kg, i.p., daily) protected retinal ganglion cells
(RGC) from cell death (
8
). In a later study from the same group,
a combination of EPO with methylprednisolone (MP), the classi-
cal anti-inflammatory therapy for the treatment of relapses in MS,
inhibited also axonal degeneration, whereas MP monotherapy,
although effective at inhibiting inflammation, slightly promoted
neurodegeneration (
9
).
In MOG-induced chronic progressive EAE in C57BL/6
mice, EPO at 50
μ
g/kg significantly decreased the clinical score
of the disease, inflammation, blood-brain barrier breakdown, and
also demyelination and axonal injury (
10
). EPO was administered
1-2 days after the disease onset (onset at day 14, EPO adminis-
tered at day 15-16), and the treatment was repeated daily for 14
days. Although given at a high dose (50
μ
g/kg), in a dose response
experiment the lowest effective dose was 500 ng/kg.
The pathological features and clinical relevance of the different
animal models of EAE have been reviewed elsewhere (
11-13
).
MOG-induced EAE in C57BL/6 mice shares with MS extensive
axonal injury, marked demyelination and a mononuclear cell
infiltrate. Axonal injury occurs early in this model. Inflammation
peaks at the maximum of disease, around day 15 post-immuniza-
tion (p.i.), and then decreases to about 20% at the later disease
phase. At day 9 p.i., at the beginning of the disease, there is already
a massive decrease of axonal densities in the lesion, which later
decrease further, decreasing also in the normal appearing white
matter. The prevalence of axonal degeneration in chronic MOG-
EAE has been recently confirmed with transmission electron
microscopy (
14
). Axonal loss seems to be dissociated from acute
inflammatory infiltration and correlates with clinical impairment
(
15
). In this model, EPO could block most of the neurological
disease progression when administered after disease onset (
10
),
μ
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