title: Brain-derived neurotrophic factor and the course of experimental cerebral malaria.
abstract: The role of neurotrophic factors on the integrity of the central nervous system (CNS) during cerebral malaria (CM) infection remains obscure, but the long-standing neurocognitive sequelae often observed in rescued children can be attributed in part to the modulation of neuronal survival and synaptic plasticity. To discriminate the contribution of key responses in the time-sequence of the pathogenic events that trigger the development of neurocognitive malaria syndrome we defined four stages (I-IV) of the neurological progression of CM in C57BL/6 mice infected with Plasmodium berghei ANKA. Upregulation of ICAM-1, VCAM-1, e-selectin and p-selectin expression was detected in all cerebral regions before parasitized red blood cells (pRBC) accumulation. As the severity of symptoms increased, BDNF mRNA progressively diminished in several brain regions, earliest in the thalamus-hypothalamus, cerebellum, brainstem and cortex, and correlated with a four-stage disease sequence. Immunohistochemical confocal microscopy revealed changes in the BDNF distribution pattern, suggesting altered axonal transport. During CM progression, molecular markers of neurological infection and inflammation in the parasite and the host, respectively, were accompanied by a switch in the brain constitutive proteasome to the immunoproteasome, which could impede normal protein turnover. In parallel with BDNF downregulation, NCAM expression also diminished with increased CM severity. Together, these data suggest that changes in BDNF availability could be involved in the pathogenesis of CM.
authors.affiliation: Department of Biochemistry and Molecular Biology IV, Universidad Complutense de Madrid, Ciudad Universitaria, 28040 Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Linares
authors.forename: Patricia
authors.initials: P
authors.lastname: Marín-García
authors.forename: Susana
authors.initials: S
authors.lastname: Pérez-Benavente
authors.forename: Jesús
authors.initials: J
authors.lastname: Sánchez-Nogueiro
authors.forename: Antonio
authors.initials: A
authors.lastname: Puyet
authors.forename: José M
authors.initials: JM
authors.lastname: Bautista
authors.forename: Amalia
authors.initials: A
authors.lastname: Diez
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D015153:Blotting, Western; D001923:Brain Chemistry / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D016207:Cytokines / Q000096:biosynthesis; D018450:Disease Progression; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000502:physiology; D016779:Malaria, Cerebral / Q000378:metabolism* / Q000469:parasitology / Q000523:psychology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019006:Neural Cell Adhesion Molecules / Q000378:metabolism; D059208:Parasite Load; D010962:Plasmodium berghei; D016133:Polymerase Chain Reaction; D046988:Proteasome Endopeptidase Complex; D012313:RNA / Q000096:biosynthesis / Q000235:genetics
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D019006:Neural Cell Adhesion Molecules; D012313:RNA; D046988:Proteasome Endopeptidase Complex