Systemic and Cerebral Vascular Endothelial Growth Factor Levels Increase in Murine Cerebral Malaria along with Increased Calpain and Caspase Activity and Can be Reduced by Erythropoietin Treatment

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.

Experimental cerebral malaria is associated with profound loss of both glycan and protein components of the endothelial glycocalyx

“…The AT3 effect on the glycocalyx was associated with normalization of plasma angiopoietin-1 and reduced BBB permeability. An increase in angiopoietin-1 is considered positive because reduced plasma levels have been closely associated with malaria severity in human and murine malaria (25,52). Whether this outcome was due to a specific effect on the glycocalyx or reduced local inflammation ( Fig.…”

“…Plasma angiopoietin-1 was quantified by using an ELISA kit (R&D Systems) according to the manufacturer's instructions in 25-50 ml of plasma, and hyaluronic acid (HA) was quantified in 60 ml of plasma (Echelon Biosciences, Salt Lake City, UT, USA), as previously described (7,25). The HA ELISA was also used to quantify HA levels in brain tissue after normalizing to protein concentration.…”

Sequestration and Histopathological Changes of the Lung, Kidney and Brain of Mice Infected with Plasmodium berghei that Exposed to Repeated Artemisinin

“…The increasing of lung edema in the control treatment group (TC) significantly different from the treatment group (T4) due to Plasmodium berghei who had been exposed to repeated anti-malarial artemisinin drugs may increase lung damage associated with its ability to activate the dependent CD36 as infected red blood cell mediator (iRBC) sequestration, since the presence of blockade on CD36 as mediated sequestration that may increase the ability of mononuclear phagocytosis so that it can be effective to clean the parasite through non opsonic phagocytosis (Lagase et al, 2016). Microvascular obstruction due to sequestration of parasites and the presence of endothelial adhesion by inflammatory responses as well as the release of pro inflammatory mediators (adhesion molecules, cytokines, chemokines) leads to increased edema in the lung (Van den Steen, 2013), In addition, pathological changes in lung in the form of hemorrhagic edema due to increased VEGF circulation (Canavese et al, 2014;Hempel et al, 2014). The increase of hemosiderin in lung in control treatment group (TC) was significantly different with control group (C).…”

VEGF: inflammatory paradoxes

“…3 Third, CM is characterized by VEGF overproduction. Plasma VEGF levels are high in CM, as reviewed in Hempel et al 4 and, clearly, VEGF is involved in malarial pathogenesis, for its cerebral 5 and its pulmonary aspects. 6 On the basis of elevated plasma levels, agents that would antagonize Ang 2 have been proposed to treat CM.…”