RAGE antagonist decreases β-amyloid, HMGB-1, RAGE expression in the brain, and prevented long-term cognitive impairment in experimental bacterial meningitis

Abstract

Abstract Bacterial meningitis is a serious infection of the central nervous system that causes learning and memory impairment. Our central hypothesis is that during meningitis, the inflammation increases the synthesis of amyloid-beta (Aβ1-42) and up regulates receptor for advanced glycation end products (RAGE). Then the Aβ-RAGE-axis triggers long-term cognitive impairment in meningitis survivors. To test this, we evaluated Aβ1-42 deposition, RAGE, and high mobility group box-1 (HMGB-1) expression in the rat brain. We evaluated the behavioural response by treating the rats with RAGE-antagonist, N-benzyl-4-chloro-N-cyclohexylbenzamide (FPS-ZM1). The animals were separated into four groups: control/saline, control/FPS-ZM1, meningitis/saline, and meningitis/FPS-ZM1 (n=10). Experimental design: male 60-day-old Wistar rats received an intracisternal injection of 10 μL of artificial cerebrospinal fluid as a placebo or an equivalent volume of Streptococcus pneumoniae suspension at concentration of 5×109 CFU/mL. Eighteen hours after meningitis induction, all animals received ceftriaxone. Ten days after inoculation all blood cultures performed were negative showing that the animals were free from infection. At 10 day after meningitis induction the results from western-blot showed increased expression of Aβ, RAGE, and HMGB-1 in the hippocampus and prefrontal cortex of meningitis group. The FPS-ZM1 adjuvant treatment prevented the Aβ1-42, RAGE, and HMGB-1 expression in both brain structures and prevented long-term memory impairment in the meningitis group. The bacterial meningitis may trigger cognitive impairment through up-regulating Aβ-RAGE axis and RAGE-antagonist prevented cognitive impairment.