RAGE inhibitor prevents cognitive dysfunction and reduces inflammatory mediators in experimental pneumococcal meningitis

Abstract The inflammatory processes during pneumococcal meningitis increase the production of inflammatory mediators culminating with increased production and deposition of amyloid proteins. Our hypothesis is that the interaction of the RAGE-Aβ can stimulate multiple intracellular signaling pathways which leads to the inflammatory mediator’s production. This can lead to neuronal damage and impairment of the integrity of the blood-brain barrier (BBB) causing memory impairment and learning. Therapeutic strategies suggest that RAGE is an important target for the treatment of inflammatory diseases, since inflammation increases Aβ synthesis and regulates RAGE positively, and the activation of this pathway induces long-term cognitive dysfunction. The aim of this study was evaluated cytokines levels; BBB integrity; behavioral response and Aβ deposition, RAGE and high mobility group box-1 (HMGB-1) expression in adult Wistar rats after meningitis induction treated with RAGE-antagonist (FPS-ZM1). To evaluate the levels of tumor necrosis factor α (TNF-α), interleukin (IL) 1β, and IL-6 the animals were killed at 24 h; for BBB integrity were killed at 12, 18 and 24 h; for the behavioral and expression of RAGE, HMGB1 and Aβ the animals received treatment with ceftriaxone and were killed within 10 days after the induction of meningitis. In the tests the inhibition of RAGE with FPS-ZM1 decreased the cytokines production only prefrontal cortex, prevented the BBB break in 12, 18 and 24 h in the hippocampus and cerebral cortex, and decreased cognitive damage 10 days after meningitis induction. We demonstrate that bacterial meningitis may trigger cognitive impairment through up-regulation RAGE axis and RAGE-antagonist prevented cognitive impairment.