Is Ischemia Involved in the Pathogenesis of Murine Cerebral Malaria?

Abstract

Sequestration of parasitized erythrocytes in the central nervous system microcirculation and increased cerebrospinal fluid lactate are prominent features of cerebral malaria (CM), suggesting that sequestration causes mechanical obstruction and ischemia. To examine the potential role of ischemia in the pathogenesis of CM, Plasmodium berghei ANKA (PbA) infection in CBA mice was compared to infection with P. berghei K173 (PbK) which does not cause CM (the non-CM model, NCM). Cerebral metabolite pools were measured by (1)H nuclear magnetic resonance spectroscopy during PbA and PbK infections. Lactate and alanine concentrations increased significantly at the terminal stage of CM, but not in NCM mice at any stage. These changes did not correlate with parasitemia. Brain NAD/NADH ratio was unchanged in CM and NCM mice at any time studied, but the total NAD pool size decreased significantly in the CM mice on day 7 after inoculation. Brain levels of glutamine and several essential amino acids were increased significantly in CM mice. There was a significant linear correlation between the time elapsed after infection and small, progressive decreases in the cell density/cell viability markers glycerophosphocholine and N-acetylaspartate in CM, indicative of gradual loss of cell viability. The metabolite changes followed a different pattern, with a sudden significant alteration in the levels of lactate, alanine, and glutamine at the time of terminal CM. In NCM, there were significant decreases with time of glutamate, the osmolyte myo-inositol, and glycerophosphocholine. These results are consistent with an ischemic change in the metabolic pattern of the brain in CM mice, whereas in NCM mice the changes were more consistent with hypoxia without vascular obstruction. Mild obstructive ischemia is a likely cause of the metabolic changes during CM, but a role for immune cell effector molecules cannot be ruled out.

Non-invasive In-cell Determination of Free Cytosolic [NAD+]/[NADH] Ratios Using Hyperpolarized Glucose Show Large Variations in Metabolic Phenotypes

“…B, a vertical zoom of A scaled to the same signal-to-noise for the two cell types. The identified signals correspond to: [2-13 C]dihydroxyacetone (212.6 ppm, dihydroxyacetone phosphate (C2-DHAP)), [ [1][2][3][4][5][6][7][8][9][10][11][12][13] C]lactate, in Human Cancer CellsDynamic nuclear polarization enhancement of NMR signals permits measurement of in-cell dynamic data. Hyperpolarized glycolytic intermediates and end products were followed with a temporal resolution of 2 s for 1 min in MCF7 and PC3 cells (Fig.…”

“…Most NADH present in the mitochondria is protein-bound (10) and will not contribute to the cellular redox potential. Whereas the total cellular [NAD ϩ ]/[NADH] ratio is typically on the order of 2-4 (11,12), the free cytosolic [NAD ϩ ]/[NADH] ratio is usually several orders of magnitude higher (13,14). Thus, the importance of the ratio of free cytosolic [NAD ϩ ]/[NADH] to the cellular redox potential has lead to a focus on methods capable of estimating this ratio.…”

FTIR Imaging of Brain Tissue Reveals Crystalline Creatine Deposits Are an ex Vivo Marker of Localized Ischemia during Murine Cerebral Malaria: General Implications for Disease Neurochemistry

“…19−24 In direct contrast to AD pathology, CM predominantly affects children under the age of five in subSaharan Africa (approximately one million deaths each year), and the disease has a rapid time-course from onset of clinical symptoms to death (less than 1 week, in both humans and animal models). 22,32−37 Previously, there was no evidence for the involvement of altered brain creatine kinase function during CM pathogenesis. 22,37−41 Despite these significant differences in pathology, the following results, which employ FTIR spectroscopic imaging for the analysis of cryofixed air-dried tissue sections, have been used to ascertain whether changes in the Cr/Cr P ratio is also common to CM.…”

Murine Cerebral Malaria Is Associated with a Vasospasm-Like Microcirculatory Dysfunction, and Survival upon Rescue Treatment Is Markedly Increased by Nimodipine

“…In murine CM, magnetic resonance imaging (MRI) and spectroscopy studies showed the presence of brain edema, decreased CBF, and ischemia. 20,21 Lack of resolution in MRI, however, precludes detailed studies of the microcirculation, which is a major target and player in CM pathogenesis. A few studies have addressed the in vivo microcirculatory changes in murine models of severe malaria, [22][23][24] however in sites other than the brain (cremaster muscle or skin).…”