title: Inhibition of matrix metalloproteinases-2 and -9 prevents cognitive impairment induced by pneumococcal meningitis in Wistar rats.
abstract: Pneumococcal meningitis is a relevant clinical disease characterized by an intense inflammatory reaction into the subarachnoid and ventricular spaces, leading to blood-brain barrier breakdown, hearing loss, and cognitive impairment. Matrix metalloproteinases (MMPs) are capable of degrading components of the basal laminin, thus contributing to BBB damage and neuronal injury. In the present study, we evaluated the effects of MMP-2, MMP-9, and MMP-2/9 inhibitors on BBB integrity, learning, and memory in Wistar rats subjected to pneumococcal meningitis. The animals underwent a magna cistern tap and received either 10 µL sterile saline as a placebo or an equivalent volume of a Streptococcus pneumoniae suspension at a concentration of 5 × 10(9)cfu/mL. The rats were randomized into different groups that received adjuvant treatment with MMP-2, MMP-9 or MMP-2/9 inhibitors. The BBB integrity was evaluated, and the animals were habituated to open-field and object recognition tasks 10 days after meningitis induction. Adjuvant treatments with inhibitors of MMP-2 or MMP-2/9 prevented BBB breakdown in the hippocampus, and treatments with inhibitors of MMP-2, MMP-9 or MMP-2/9 prevented BBB breakdown in the cortex. Ten days after meningitis induction, the animals that received adjuvant treatment with the inhibitor of MMP-2/9 demonstrated that animals habituated to the open-field task faster and enhanced memory during short-term and long-term retention test sessions in the object recognition task. Further investigation is necessary to provide support for MMP inhibitors as an alternative treatment for bacterial meningitis; however, these findings suggest that the meningitis model could be a good research tool for studying the biological mechanisms involved in the behavioral alterations associated with pneumococcal meningitis.
authors.affiliation: Laboratório de Microbiologia Experimental, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense, 88806-000 Criciúma, SC, Brazil.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Barichello
authors.forename: Jaqueline S
authors.initials: JS
authors.lastname: Generoso
authors.forename: Cleonice M
authors.initials: CM
authors.lastname: Michelon
authors.forename: Lutiana R
authors.initials: LR
authors.lastname: Simões
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Elias
authors.forename: Franciele
authors.initials: F
authors.lastname: Vuolo
authors.forename: Clarissa M
authors.initials: CM
authors.lastname: Comim
authors.forename: Felipe
authors.initials: F
authors.lastname: Dal-Pizzol
authors.forename: João
authors.initials: J
authors.lastname: Quevedo
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000382:microbiology / Q000503:physiopathology; D003072:Cognition Disorders / Q000209:etiology / Q000517:prevention & control*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007858:Learning / Q000187:drug effects; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000627:therapeutic use*; D008568:Memory / Q000187:drug effects; D008586:Meningitis, Pneumococcal / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013296:Streptococcus pneumoniae
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9
keywords: Meningitis; Streptococcus pneumoniae; blood–brain barrier; learning and memory; metalloproteinases-2 and 9