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.