title: Matrix metalloproteinase-2 and metalloproteinase-9 activities are associated with blood-brain barrier dysfunction in an animal model of severe sepsis.
abstract: There is no description on the mechanisms associated with blood-brain barrier (BBB) disruption during sepsis development. Thus, we here determined changes in permeability of the BBB in an animal model of severe sepsis and the role of matrix metalloproteinase (MMP)-2 and MMP-9 in the dysfunction of the BBB. Sepsis was induced in Wistar rats by cecal ligation and perforation. BBB permeability was assessed using the Evans blue dye method. The content of MMP-2 and MMP-9 in the cerebral microvessels was determined by western blot. The activity of MMP-2 and MMP-9 was determined using zymography. An inhibitor of MMP-2 and MMP-9 or specific inhibitors of MMP-2 or MMP-9 were administered to define the role of MMPs on BBB permeability, brain inflammatory response, and sepsis-induced cognitive alterations. The increase of BBB permeability is time-related to the increase of MMP-9 and MMP-2 in the microvessels, both in cortex and hippocampus. Using an MMP-2 and MMP-9 inhibitor, or specific MMP-2 or MMP-9 inhibitors, the increase in the permeability of the BBB was reversed. This was associated with lower brain levels of interleukin (IL)-6 and lower oxidative damage. In contrast, only the inhibition of both MMP-9 and MMP-2 was able to improve acute cognitive alterations associated with sepsis. In conclusion, MMP-2 and MMP-9 activation seems to be a major step in BBB dysfunction, but BBB dysfunction seems not to be associated with acute cognitive dysfunction during sepsis development.
authors.affiliation: Laboratório de Fisiopatologia Experimental and Instituto Nacional de Ciência e Tecnologia Translacional em Medicina, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, 88806-000, Criciúma, SC, Brazil. fdpizzol@gmail.com
authors.forename: Felipe
authors.initials: F
authors.lastname: Dal-Pizzol
authors.forename: Hugo Alberto
authors.initials: HA
authors.lastname: Rojas
authors.forename: Emilia Marcelina
authors.initials: EM
authors.lastname: dos Santos
authors.forename: Francieli
authors.initials: F
authors.lastname: Vuolo
authors.forename: Larissa
authors.initials: L
authors.lastname: Constantino
authors.forename: Gustavo
authors.initials: G
authors.lastname: Feier
authors.forename: Matheus
authors.initials: M
authors.lastname: Pasquali
authors.forename: Clarissa M
authors.initials: CM
authors.lastname: Comim
authors.forename: Fabrícia
authors.initials: F
authors.lastname: Petronilho
authors.forename: Daniel Pens
authors.initials: DP
authors.lastname: Gelain
authors.forename: João
authors.initials: J
authors.lastname: Quevedo
authors.forename: José Cláudio Fonseca
authors.initials: JC
authors.lastname: Moreira
authors.forename: Cristiane
authors.initials: C
authors.lastname: Ritter
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D055806:Microvessels / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9