title: Quantitation of brain edema and localisation of aquaporin 4 expression in relation to susceptibility to experimental cerebral malaria.
abstract: The pathogenic mechanisms underlying the occurrence of cerebral malaria (CM) are still incompletely understood but, clearly, cerebral complications may result from concomitant microvessel obstruction and inflammation. The extent to which brain edema contributes to pathology has not been investigated. Using the model of P. berghei ANKA infection, we compared brain microvessel morphology of CM-susceptible and CM-resistant mice. By quantitative planimetry, we provide evidence that CM is characterized by enlarged perivascular spaces (PVS). We show a dramatic aquaporin 4 (AQP4) upregulation, selectively at the level of astrocytic foot processes, in both CM and non-CM disease, but significantly more pronounced in mice with malarial-induced neurological syndrome. This suggests that a threshold of AQP4 expression is needed to lead to neurovascular pathology, a view that is supported by significantly higher levels in mice with clinically overt CM. Numbers of intravascular leukocytes significantly correlated with both PVS enlargement and AQP4 overexpression. Thus, brain edema could be a contributing factor in CM pathogenesis and AQP4, specifically in its astrocytic location, a key molecule in this mechanism. Since experimental CM is associated with substantial brain edema, it models paediatric CM better than the adult syndrome and it is tempting to evaluate AQP4 in the former context. If AQP4 changes are confirmed in human CM, it may represent a novel target for therapeutic intervention.
authors: Vascular Immunology Unit, Dept. of Pathology, Faculty of Medicine and Bosch Institute, University of Sydney, Sydney, Australia.
authors: Sumate
authors: S
authors: Ampawong
authors: Valéry
authors: V
authors: Combes
authors: Nicholas H
authors: NH
authors: Hunt
authors: Jane
authors: J
authors: Radford
authors: Tailoi
authors: T
authors: Chan-Ling
authors: Emsri
authors: E
authors: Pongponratn
authors: Georges E R
authors: GE
authors: Grau
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism / Q000469:parasitology / Q000473:pathology*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000469:parasitology; D001929:Brain Edema / Q000378:metabolism / Q000469:parasitology / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D007962:Leukocytes / Q000378:metabolism / Q000473:pathology; D016779:Malaria, Cerebral / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D010962:Plasmodium berghei; D013045:Species Specificity; D015854:Up-Regulation
chemical_list: C496031:Aqp4 protein, mouse; D051401:Aquaporin 4; D015415:Biomarkers