Biology Reference
In-Depth Information
combined to with thrombolysis therapy (i.v. rt-PA injection) (
60
).
Anyhow due to the adverse effects associated with long-term
rhEPO administration, such as hypertension or thrombosis, exper-
imental research focused on the dissociated effect of EPO and the
future clinical application of EPO may be based on the use of new
EPO derivatives (
63, 69-71
). Therefore, several engineered EPO
derivatives have cytoprotective effects, but do not stimulate
significant erythropoiesis (
72
). All the hematopoietic effects engen-
dered by EPO on the bone marrow are mediated by the homodi-
meric EPOR (
69
). Desialylated EPO (or asialo EPO, generated by
total enzymatic desialylation of rhEPO) can bind to the mature
EPOR with the same EPOR affinity, but its very shorter plasma
half-life allows reducing the hematopoietic response while main-
taining its neuroprotective effects. In contrast, the second genera-
tion of EPO molecule, carbamylated EPO (CEPO, with all lysines
transformed to homocitrulline by carbamylation) does not bind to
the homodimeric EPOR and lacks erythropoietic activity but could
confer neuroprotection. It has been suggested that EPO and
CEPO neuroprotective effects might be mediated by a common
beta receptor (bR), which can form a dimer with EPOR (EPOR-
bR). At the moment, those non-erythropoietic EPO derivatives
were tested in preclinical studies and show some promising results
(
71, 73-77
). The neuroprotective effects of EPO and non-
hematopoietic derivatives of EPO have been shown in different
studies thanks to the use of these experimental stroke models.
Table
1
summarizes the results coming from those studies. In par-
allel, two clinical trials (phase I) have been conducted to access the
safety and the pharmacokinetic of CEPO administration to patients
who have suffered an ischemic stroke.
In this methodological section we describe two procedures to
induce experimental ischemia. The model of intraluminal filament
occlusion and the model of permanent electrocoagulation are
widely used in the literature to study the physiopathology of stroke
and the efficiency of therapeutic strategies. They have been used to
evaluate the potential neuroprotective effect of cytokines on cere-
bral ischemia. Table
1
summarizes the results coming from those
studies. The neuroprotective effect of EPO and non-hematopoietic
derivatives of EPO has been shown in different studies thanks to
the use of experimental models of stroke in animals.
3.4.3
Conclusion
4
Notes
1. The age of the animal is important. To mimic stroke occur-
rence in adult human, it is required to work with at least adult
animals (3 months or more for rats). This even if the impact of
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