Reduced cerebral blood flow and N-acetyl aspartate in a murine model of cerebral malaria

Abstract

Cerebral malaria is an important cause of morbidity and mortality in many parts of the world. It has been suggested that cerebral malaria is associated with reduced perfusion due to the blockage of blood vessels by parasitized erythrocytes; although, no quantitative validation of this has been done. We infected C57BL/6 mice with the ANKA strain of Plasmodium berghei and on day 6 of infection we investigated alterations in brain function using arterial spin labeling MRI and proton MRS. MR images did not demonstrate signs of damage. However, there was a significant reduction in cerebral blood flow (P<0.012) and the ratio of N-acetyl-aspartate (NAA) to creatine (Cr) (P<0.01) relative to non-infected mice. The NAA/Cr ratios were significantly correlated with cerebral perfusion (r=0.87) suggesting a relationship between impaired oxygen delivery and neuronal dysfunction. Pathological examination revealed accumulations of damaged axons providing a correlate for the decreased NAA/Cr ratio in infected mice. This murine model will permit non-invasive studies of neurologic function during malarial infection.

Endothelin-1 and its role in the pathogenesis of infectious diseases

“…Moreover, experimental CM displayed significant increases in ET-1 mRNA expression in the brain correlating to human findings [15]. This increase in the ET system was associated with glial activation, neuronal damage, and a reduction in CBF [15, 84]. Interestingly, ET-1 administration in the left middle cerebral artery in rats results in a dose dependent reduction in CBF and in ischemic brain damage [93].…”

Fatal cerebral malaria: a venous efflux problem

“…Using intravital microscopy (IVM), we found more platelets, CD8+ T cells, neutrophils, and macrophages accumulated in postcapillary venules (PCV) from PbA-infected mice with ECM compared to P. yoelii XL (PyXL)-infected mice, which develop hyperparasitemia without neurological signs (Nacer et al, 2012, in press). In mice with symptomatic ECM, leukocyte adhesion reduced the functional vascular cross-section of PCV and larger venules significantly and this can explain the reduced cerebral blood flow observed by MRI (Kennan et al, 2005). Supporting our findings, nitric oxide, a key messenger involved in regulation of platelet adhesion and inflammatory and immune responses (Willenborg et al, 2007), decreased both leukocyte accumulation and vascular resistance in venules of PbA-infected mice (Cabrales et al, 2011; Hawkes et al, 2011).…”

The immunological balance between host and parasite in malaria

“…In both P. falciparum-infected patients and mice with severe malaria infections, heterogeneous obstruction of microcirculatory blood flow was recorded, and the degree of obstruction was proportional to the extent of ischemia and to the disease severity (Kennan et al 2005;Penet et al 2005;Dondorp et al 2008;Beare et al 2009;Cabrales et al 2010;Hanson et al 2012;Ponsford et al 2012;Cabrales et al 2013). In P. falciparum-infected patients with CM, massive iRBC cytoadherence is observed in the brain microvasculature (Silamut et al 1999;Milner et al 2014).…”

“…Furthermore, tissue macrophages e.g. microglia, Kupffer cells and alveolar macrophages, are activated during infection in mice and humans (Medana, Hunt and ChanLing 1997;Schluesener, Kremsner and Meyermann 1998;Clark et al 2003, Kennan et al 2005Pais and Chatterjee 2005;Whitten et al 2011). Widespread microglial activation is not limited to areas of petechial bleedings or iRBC sequestration and precedes accumulation of leukocytes and in situ proliferation of CD8 + T cells (Schluesener, Kremsner and Meyermann 1998;Pais and Chatterjee 2005).…”