title: Lactate transport and receptor actions in cerebral malaria.
abstract: Cerebral malaria (CM), caused by Plasmodium falciparum infection, is a prevalent neurological disorder in the tropics. Most of the patients are children, typically with intractable seizures and high mortality. Current treatment is unsatisfactory. Understanding the pathogenesis of CM is required in order to identify therapeutic targets. Here, we argue that cerebral energy metabolic defects are probable etiological factors in CM pathogenesis, because malaria parasites consume large amounts of glucose metabolized mostly to lactate. Monocarboxylate transporters (MCTs) mediate facilitated transfer, which serves to equalize lactate concentrations across cell membranes in the direction of the concentration gradient. The equalizing action of MCTs is the basis for lactate's role as a volume transmitter of metabolic signals in the brain. Lactate binds to the lactate receptor GPR81, recently discovered on brain cells and cerebral blood vessels, causing inhibition of adenylyl cyclase. High levels of lactate delivered by the parasite at the vascular endothelium may damage the blood-brain barrier, disrupt lactate homeostasis in the brain, and imply MCTs and the lactate receptor as novel therapeutic targets in CM.
authors.affiliation: Department of Neuroscience and Pharmacology, University of Copenhagen Copenhagen, Denmark.
authors.forename: Shelton T
authors.initials: ST
authors.lastname: Mariga
authors.affiliation: Department of Neuroscience and Pharmacology, University of Copenhagen Copenhagen, Denmark ; Department of Ophthalmology, Roskilde Hospital Roskilde, Denmark.
authors.forename: Miriam
authors.initials: M
authors.lastname: Kolko
authors.affiliation: Department of Neuroscience and Pharmacology, University of Copenhagen Copenhagen, Denmark.
authors.forename: Albert
authors.initials: A
authors.lastname: Gjedde
authors.affiliation: Department of Neuroscience and Pharmacology, University of Copenhagen Copenhagen, Denmark ; The Brain and Muscle Energy Group and SN-Lab, Department of Anatomy and Department of Oral Biology, Institute of Basic Medical Sciences and Centre for Molecular Biology and Neuroscience/SERTA Healthy Brain Aging Centre, University of Oslo Oslo, Norway.
authors.forename: Linda H
authors.initials: LH
authors.lastname: Bergersen
keywords: cerebral malaria; energy metabolism; lactate receptor; lactate transport; volume transmitter