Is ischemia involved in the pathogenesis of murine cerebral malaria?

Sequestration of parasitized erythrocytes in the central nervous system mic rocirculation and increased cerebrospinal fluid Lactate are prominent featu res of cerebral malaria (CM), suggesting that sequestration causes mechanic al obstruction and ischemia. To examine the potential role of ischemia in t he pathogenesis of CM, Plasmodium berghei ANKA (PbA) infection in CBA mice was compared to infection with P. berghei K173 (PbK) which does not cause C M (the non-CM model, NCM). Cerebral metabolite pools were measured by H-1 n uclear magnetic resonance spectroscopy during PbA and PbK infections. Lacta te and alanine concentrations in creased significantly at the terminal stag e of CM, but not in NCM mice at any stage. These changes did not correlate with parasitemia. Brain NAD/NADH ratio was im changed in CM and NCM mice at any time studied, but the total NAD pool size decreased significantly in t he CM mice on day 7 after inoculation. Brain levels of glutamine and severa l essential amino acids were increased significantly in CM mice. There was a significant linear correlation between the time elapsed after infection a nd small, progressive decreases in the cell density/cell viability markers glycerophosphocholine and N-acetylaspartate in CM, indicative of gradual lo ss 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 decre ases with time of glutamate, the osmolyte myo-inositol, and glycerophosphoc holine. These results are consistent with an ischemic change in the metabol ic pattern of the brain in CM mice, whereas in NCM mice the changes were mo re consistent with hypoxia without vascular obstruction. Mild obstructive i schemia is a likely cause of the metabolic changes during CM, but a role fo r immune cell effector molecules cannot be ruled out.