Receptor for Advanced Glycation End Products (RAGE) Mediates Cognitive Impairment Triggered by Pneumococcal Meningitis
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ORIGINAL ARTICLE
Receptor for Advanced Glycation End Products (RAGE) Mediates Cognitive Impairment Triggered by Pneumococcal Meningitis Vijayasree V. Giridharan 1 & Jaqueline S. Generoso 2 & Allan Collodel 2 & Diogo Dominguini 2 & Cristiano Julio Faller 2 & Flavio Tardin 2 & Gursimrat S. Bhatti 1 & Fabricia Petronilho 3 & Felipe Dal-Pizzol 2 & Tatiana Barichello 1,2
# The American Society for Experimental NeuroTherapeutics, Inc. 2020
Abstract Pneumococcal meningitis is a life-threatening infection of the central nervous system (CNS), and half of the survivors of meningitis suffer from neurological sequelae. We hypothesized that pneumococcal meningitis causes CNS inflammation via the disruption of the blood–brain barrier (BBB) and by increasing the receptor for advanced glycation end product (RAGE) expression in the brain, which causes glial cell activation, leading to cognitive impairment. To test our hypothesis, 60-day-old Wistar rats were subjected to meningitis by receiving an intracisternal injection of Streptococcus pneumoniae or artificial cerebrospinal fluid as a control group and were treated with a RAGE-specific inhibitor (FPS-ZM1) in saline. The rats also received ceftriaxone 100 mg/kg intraperitoneally, bid, and fluid replacements. Experimental pneumococcal meningitis triggered BBB disruption after meningitis induction, and FPS-ZM1 treatment significantly suppressed BBB disruption. Ten days after meningitis induction, surviving animals were free from infection, but they presented increased levels of TNF-α and IL-1β in the prefrontal cortex (PFC); high expression levels of RAGE, amyloid-β (Aβ1–42), and microglial cell activation in the PFC and hippocampus; and memory impairment, as evaluated by the open-field, novel object recognition task and Morris water maze behavioral tasks. Targeted RAGE inhibition was able to reduce cytokine levels, decrease the expression of RAGE and Aβ1–42, inhibit microglial cell activation, and improve cognitive deficits in meningitis survivor rats. The sequence of events generated by pneumococcal meningitis can persist long after recovery, triggering neurocognitive decline; however, RAGE blocker attenuated the development of brain inflammation and cognitive impairment in experimental meningitis. Key Words Pneumococcal meningitis . RAGE . amyloid-β . blood–brain barrier . inflammation . cognition
Introduction
Vijayasree V. Giridharan and Jaqueline S. Generoso contributed equally to this work. * Tatiana Barichello [email protected] 1
Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, 1941 East Road, Houston, TX 77054, USA
2
Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, University of Southern Santa Catarina (UNESC), Criciúma 88806-000, SC, Brazil
3
Laboratory of Neurobiology of Inflammatory and Metabolic Processes, Graduate Program in Health Sciences, Health Sciences Unit, University of South Santa Catarina, T
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