Is ischemia involved in the pathogenesis of murine cerebral malaria?
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.
Sanni
L A
LA
Department of Pathology, University of Sydney, Sydney, Australia.
Rae
C
C
Maitland
A
A
Stocker
R
R
Hunt
N H
NH
D000255:Adenosine Triphosphate / Q000378:metabolism; D000409:Alanine / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000150:complications* / Q000175:diagnosis; D002851:Chromatography, High Pressure Liquid; D005260:Female; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D016779:Malaria, Cerebral / Q000175:diagnosis / Q000209:etiology*; D051379:Mice; D008808:Mice, Inbred CBA; D009243:NAD / Q000378:metabolism; D009994:Osmolar Concentration; D019289:Pyruvic Acid / Q000378:metabolism
D000596:Amino Acids; D009243:NAD; D019344:Lactic Acid; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D000409:Alanine