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.
Recent findings that levels of brain lactate and alanine were elevated in murine cerebral malaria led us to investigate the effect of dichloroacetate (DCA; 60 mg/kg), an activator of pyruvate dehydrogenase, on the levels of brain metabolites, and on the survival of mice infected with Plasmodium berghei ANKA which normally causes lethal cerebral malaria. DCA significantly reduced brain lactate and alanine levels when administered to infected mice, had no effect on the TCA cycle-related metabolites glutamate, GABA and aspartate and was associated with increased brain glutamine levels: 40% of mice thus treated survived the normally lethal infection.
Cerebral malaria (CM) is the major life-threatening complication of Plasmodium falciparum infecti0n.A prominent clinical feature of human CM is increased lactate in both brain and cerebrospinal fluid, with sustained lactic acidosis being an important prognostic indicator. To investigate whether DCA, an activator of the pyruvate dehydrogenase complex, ameliorates lactic acidosis in the murine model of CM,Plasmodium bergheiANKA infection in CBA mice was studied in animals injected with DCA (60mg/kg)on days 5 and 6 post-inoculation (pi). On day 7 p.i. some animals were injected intravenously with [13C]-glucose and sacrificed after 15 and 30 min. Cerebral metabolites were analysed using both 13C and IH-NMR spectroscopy.Brain metabolite pool sizes in PbA/CBA mice showed definite metabolic perturbation, including significant increases in Lac and Ala, indicative of ischaemia, together with GABA and Gln. 13C-NMR analysis of brain metabolism in these mice indicated a marked decrease in TCA cycle activity together with a compensatory increase in glycolysis.DCA treatment provided significant TCA cycle recovery with 13C enrichment of Glu and Gln C2,3 & 4 isotopomers reverting to control profiles.Total pool sizes for Glu and Gln increased significantly over control levels.Lac and Ala pool sizes, although still elevated, were signifcantly decreased in comparison to untreated, PbA/CBA mice.In short, DCA improved neurological outcome in CBA mice infected with PbA, perhaps through providing a beneficial decrease in acidosis and facilitating recovery of aerobic metabolism. Retinoid nuclear and c-erbB membrane receptor signaling control mammary epithelial cell proliferation, differentiation and morphology. Here, we examined the morphogenetic activities of retinoids and of c-erbB specific ligands such as heregulin p l (HRG) alone or in combination on primary human mammary epithelial cells (HMEC), on the nonmalignant human mammary epithelial cell line MTSV 1-7 and on two breast cancer cell lines (SK-BR-3, T47D) cultivated in 3D collagen gels. HMEC spontaneously formed branched ducts, whereas MTSV 1-7 required retinoid for branching. Retinoids alone did not reveal any morphogenetic activity on breast cancer cells. HRG, however, was morphologically active, leading to formation of compact 'acini'-like structures. More importantly, treatment with retinoids and HRG resulted in the formation of branched ducts, indicating that retinoids can augmenuextend HRGinduced morphogenesis in breast cancer cells. Flow cytometty and immunofluorescence microscopy revealed that these morphological responses were accompanied with changes in the distribution of differentiation markers such as a2p I-integrin (the major collagen receptor) and of E-cadherin. Retinoids and HRG correspondingly increased the specific adhesion of SK-BR-3 cells to type I collagen, but not to unspecific substrates such as ply-D-lysine. Our data demonstrate cooperative signaling of retinoid and c-erbB receptor pathways at several functional levels including morphogenesis and immunop...
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