Abstract
The pathogenesis of cerebral malaria (CM) includes compromised microvascular perfusion, increased inflammation, cytoadhesion, and endothelial activation. These events cause blood–brain barrier disruption and neuropathology and associations with the vascular endothelial growth factor (VEGF) signaling pathway have been shown. We studied this pathway in mice infected with Plasmodium berghei ANKA causing murine CM with or without the use of erythropoietin (EPO) as adjunct therapy. ELISA and western blotting was used for quantification of VEGF and relevant proteins in brain and plasma. CM increased levels of VEGF in brain and plasma and decreased plasma levels of soluble VEGF receptor 2. EPO treatment normalized VEGF receptor 2 levels and reduced brain VEGF levels. Hypoxia-inducible factor (HIF)-1α was significantly upregulated whereas cerebral HIF-2α and EPO levels remained unchanged. Furthermore, we noticed increased caspase-3 and calpain activity in terminally ill mice, as measured by protease-specific cleavage of α-spectrin and p35. In conclusion, we detected increased cerebral and systemic VEGF as well as HIF-1α, which in the brain were reduced to normal in EPO-treated mice. Also caspase and calpain activity was reduced markedly in EPO-treated mice.
Highlights
Cerebral malaria (CM) is one of the most severe complications of malaria causing substantial morbidity and mortality mainly in Sub-Saharan Africa [1]
It has been claimed that this model is a poor replicate of human CM [40] and P. berghei ANKA does not export the same variant surface antigens to the erythrocyte surface as in Plasmodium falciparum malaria [2] and studies focussed on cerebral sequestration can not be performed using the rodent model
Increased plasma levels of vascular endothelial growth factor (VEGF) was shown to be responsible for acute lung injury in another murine model of malaria [28], but VEGF signaling has not been addressed in murine CM
Summary
Cerebral malaria (CM) is one of the most severe complications of malaria causing substantial morbidity and mortality mainly in Sub-Saharan Africa [1]. Due to the apparent cerebral hypoxia in human and murine CM [3,4,5,6], adjunctive strategies, which aim to overcome this, could potentially improve outcome. One of the HIF-regulated proteins is the pleiotropic cytokine erythropoietin (EPO) mainly regulated by HIF-2α [11]. EPO has been associated with protection of cells and tissue beyond the hematopoietic lineage [12, 13]. It improves survival in murine CM [5, 14,15,16] and is a safe adjunctive treatment in Malian children [17]. The cerebral hypoxia detectable in terminally ill CM mice was reversed by exogenous EPO treatment [5]
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