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Fig. 4
Thionin histological staining on a slice of rat brain previously subjected to intraluminal MCAO
Among all the neuroprotective strategies developed and tested,
several tissue-protective cytokines have been pointed out in the lit-
erature. Erythropoietin (EPO) is one of the neuroprotective cytok-
ines but other strategies involving other cytokines, like the inhibition
of interleukin-1, showed promising results. The rational for a neuro-
protective effect of EPO was sustained by the existence of an endog-
enous expression of EPO and its receptor (EPOR) in the brain with
an increase in expression rate of EPO and EPOR after a stroke.
Accordingly, since the last decade, a neuroprotective effect of EPO
has first been suggested in rats subjected to global ischemia (
56
) and
in permanent focal ischemia in mice (
57
). Since those determining
investigations, EPO treatment has shown promising features for
acute treatment of brain ischemia (
58-62
). Local cerebral adminis-
tration of rhEPO prevents ischemia-induced learning disability and
neuronal death (
57, 63
). Those studies suggest different mecha-
nisms underlying the neuroprotective actions of EPO independently
of its hematopoietic action (
56, 64-67
) such as a reduction of the
formation of free radicals, an anti-apoptotic activity, reduction of
intracellular Ca
2+
in the excitotoxic condition.
Since the realization that EPO has neuroprotective properties
in numerous preclinical studies, it has been investigated as treat-
ments for acute ischemic stroke. The first clinical trial was initiated
in 2002. In this trial, 13 patients suffering from MCA occlusion
and arriving less than 8 h after onset, received EPO intravenously
daily for 3 days following stroke onset. This trial showed the
absence of side effects and suggested a slight improvement of the
functional recovery (using two different neurological scores), but
without impact on the lesion size (
61, 68
). Following this pioneer
clinical study, another randomized German Multicenter EPO
Stroke Trial was designed on more than 500 patients to evaluate
efficacy and safety of EPO in stroke. However, this time, the results
published in 2009 were disappointing, showing inefficiency of
EPO treatment or even an increase in the mortality rate when
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