Brain gene expression, metabolism, and bioenergetics: interrelationships in murine models of cerebral and noncerebral malaria

Abstract

Malaria infection can cause cerebral symptoms without parasite invasion of brain tissue. We examined the relationships between brain biochemis¬try, bioenergetics, and gene expression in murine mod¬els of cerebral ( Plasmodium berghei ANKA) and nonce¬rebral ( P. berghei K173) malaria using multinuclear NMR spectroscopy, neuropharmacological approaches, and real‐time RT‐PCR. In cerebral malaria caused by P. berghei ANKA infection, we found biochemical changes consistent with increased glutamatergic activity and decreased flux through the Krebs cycle, followed by increased production of the hypoxia markers lactate and alanine. This was accompanied by compromised brain bioenergetics. There were few significant changes in expression of mRNA for metabolic enzymes or transporters or in the rate of transport of glutamate or glucose. However, in keeping with a role for endoge¬nous cytokines in malaria cerebral pathology, there was significant up‐regulation of mRNAs for TNF‐α, inter¬feron‐γ, and lymphotoxin. These changes are consis¬tent with a state of cytopathic hypoxia. By contrast, in P. berghei K173 infection the brain showed increased metabolic rate, with no deleterious effect on bioenergetics. This was accompanied by mild up‐regulation of expression of metabolic enzymes. These changes are consistent with benign hypermetabolism whose cause remains a subject of speculation.—Rae, C., McQuillan, J. A., Parekh, S. B., Bubb, W. A., Weiser, S., Balcar, V. J., Hansen, A., Ball, H., Hunt, N. H. Brain gene expression, metabolism, and bioenergetics: interrela¬tionships in murine models of cerebral and noncerebral malaria.