Prolonged survival of a murine model of cerebral malaria by kynurenine pathway inhibition.

C57BL/6J mice infected with Plasmodium berghei ANKA develop neurological dysfunction and die within 7 days of infection. We show that treatment of infected mice with a kynurenine-3-hydroxylase inhibitor prevents them from developing neurological symptoms and extends their life span threefold until severe anemia develops.

Tryptophan metabolites and brain disorders.

Tryptophan is metabolised primarily along the kynurenine pathway, of which two components are now known to have marked effects on neurons in the central nervous system. Quinolinic acid is an agonist at the population of glutamate receptors which are sensitive to N-methyl-D-aspartate (NMDA), and kynurenic acid is an antagonist at several glutamate receptors. Consequently quinolinic acid can act as a neurotoxin while kynurenic acid is neuroprotectant. A third kynurenine, 3-hydroxykynurenine, can generate free radicals and contribute to, or exacerbate, neuronal damage. Changes in the absolute or relative concentrations of these kynurenines have been implicated in a variety of central nervous system disorders such as the AIDS-dementia complex and Huntington's disease, raising the possibility that interference with their actions or synthesis could lead to new forms of pharmacotherapy for these conditions.

Neuropeptide-containing cells in the cortex and striatum of mice with cerebral malaria.

Central nervous system tissue of mice infected with Plasmodium berghei ANKA (PbA) exhibits similar histopathological features to those in post-mortem human cerebral malaria (CM) tissue. In this study, the neurochemical characteristics of PbA-infected and control mice were compared. Substance P-containing neurones were almost completely lost from the cortex and striatum of PbA-infected mice seven days after inoculation, whereas the intensity of calbindin immunolabelling was increased compared with controls. Neuropeptide Y- and somatostatin-containing neurones were dramatically reduced in number only in the cortex of day 7 post-inoculation mice compared with controls. This neurochemical pattern in mice with CM is similar to that previously reported to be produced in rats by quinolinic acid. Since the level of quinolinic acid is known to be raised in the brains of PbA-infected mice, the results would be consistent with a role for quinolinic acid in the production of brain damage in fatal murine CM.