title: Spatial reference memory deficits precede motor dysfunction in an experimental autoimmune encephalomyelitis model: the role of kallikrein-kinin system.
abstract: Multiple sclerosis (MS) is a progressive T cell-mediated autoimmune demyelinating inflammatory disease of the central nervous system (CNS). Although it is recognized that cognitive deficits represent a manifestation of the disease, the underlying pathogenic mechanisms remain unknown. Here we provide evidence of spatial reference memory impairments during the pre-motor phase of experimental autoimmune encephalomyelitis (EAE) in mice. Specifically, these cognitive deficits were accompanied by down-regulation of choline acetyltransferase (ChAT) mRNA expression on day 5 and 11 post-immunization, and up-regulation of inflammatory cytokines in the hippocampus and prefrontal cortex. Moreover, a marked increase in B1R mRNA expression occurred selectively in the hippocampus, whereas protein level was up-regulated in both brain areas. Genetic deletion of kinin B1R attenuated cognitive deficits and cholinergic dysfunction, and blocked mRNA expression of both IL-17 and IFN-γ in the prefrontal cortex, lymph node and spleen of mice subjected to EAE. The discovery of kinin receptors, mainly B1R, as a target for controlling neuroinflammatory response, as well as the cognitive deficits induced by EAE may foster the therapeutic exploitation of the kallikrein-kinin system (KKS), in particular for the treatment of autoimmune disorders, such as MS, mainly during pre-symptomatic phase.
authors.affiliation: Laboratory of Autoimmunity and Immunopharmacology, Campus Araranguá, Universidade Federal de Santa Catarina, 88900-000 Araranguá, SC, Brazil; Department of Pharmacology, Centre of Biological Sciences, Universidade Federal de Santa Catarina, 88049-900 Florianópolis, SC, Brazil. Electronic address: rafael.dutra@ufsc.br.
authors.forename: Rafael C
authors.initials: RC
authors.lastname: Dutra
authors.forename: Eduardo L G
authors.initials: EL
authors.lastname: Moreira
authors.forename: Thaís B
authors.initials: TB
authors.lastname: Alberti
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Marcon
authors.forename: Rui D
authors.initials: RD
authors.lastname: Prediger
authors.forename: João B
authors.initials: JB
authors.lastname: Calixto
mesh_terms: D000818:Animals; D002795:Choline O-Acetyltransferase / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology*; D005260:Female; D006624:Hippocampus / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000235:genetics; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000235:genetics; D016234:Kallikrein-Kinin System / Q000235:genetics / Q000276:immunology*; D008569:Memory Disorders / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009069:Movement Disorders / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011897:Random Allocation; D043783:Receptor, Bradykinin B1 / Q000172:deficiency / Q000235:genetics; D043782:Receptor, Bradykinin B2 / Q000819:agonists / Q000172:deficiency / Q000235:genetics; D013037:Spatial Behavior; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D020381:Interleukin-17; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D007371:Interferon-gamma; D002795:Choline O-Acetyltransferase
keywords: Choline acetyltransferase (ChAT); Cognitive dysfunction; Experimental autoimmune encephalomyelitis (EAE); Genetic deletion – kinin B(1)R; Multiple sclerosis