Biology Reference
In-Depth Information
Chapter 19
Cerebral Malaria: Protection by Erythropoietin
Anne-Lise Bienvenu and Stephane Picot
Abstract
Cerebral malaria (CM) is still responsible for unacceptable death rate, while new antimalarial drugs were
recently developed. CM pathophysiology shares essential biological features with cerebral ischemia.
Because erythropoietin (Epo) was demonstrated to reduce mortality rate during experimental cerebral
ischemia (1), in the early 2000, we wondered whether Epo could help to reduce the burden of CM. There
is now evidence that Epo high doses could prevent early mortality during cerebral malaria. This evidence
was obtained first using mice model of cerebral malaria, and later confirmed by prospective clinical trial in
endemic area. High doses of Epo are needed to cross the blood-brain barrier (see Note 1) and to favor the
cytoprotective versus hematopoietic effect of this pleiotropic cytokine (see Note 2).
Key words
Erythropoietin, Cerebral malaria, Neuronal apoptosis, Endothelial apoptosis, Murine
model, Neuroprotection, CEPO, Epo-biosimilars
1
Introduction
Intravenous artesunate is now the first line treatment for severe
P
.
falciparum
malaria due to high antimalarial activity and low tox-
icity (
2
). Despite the use of these highly effective drugs, 10-20%
mortality rate still occurs mostly within the first 24 h of the disease
(
3
) and more in remote endemic areas.
Adjunctive therapies during cerebral malaria (pentoxifyllin,
anti-TNF antibody, and deferoxamine) were previously tested, but
no clear evidence for increase in survival rate was provided (
4-6
).
High doses recombinant human erythropoietin are increas-
ingly used for cytoprotective properties (
1
,
7
) in order to prevent
cell and tissue injury during acute ischemic diseases (e.g., stroke),
neurological chronic diseases (e.g., Alzheimer) or acute neurologi-
cal infections (e.g., meningitis). For most of the cases, first evi-
dence of Epo cytoprotective effects was demonstrated using murine
models of the disease, and later confirmed in humans.
For cerebral malaria, the accuracy of the murine model has
been subjected to debate for a while. It is clear that difference
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