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The receptor for advanced glycation end products (RAGE) is a protein of the immunoglobulin superfamily capable of regulating inflammation. Considering the role of this receptor in the initiation and establishment of neuroinflammation, and the limited understanding of the function of RAGE in the maintenance of this condition, this study describes the effects of RAGE inhibition in the brain, through an intranasal treatment with the antagonist FPS‐ZM1, in an animal model of chronic neuroinflammation induced by acute intraperitoneal injection of lipopolysaccharide (LPS). Seventy days after LPS administration (2 mg/kg, i.p.), Wistar rats received, intranasally, 1.2 mg of FPS‐ZM1 over 14 days. On days 88 and 89, the animals were submitted to the open‐field test and were killed on day 90 after the intraperitoneal injection of LPS. Our results indicate that blockade of encephalic RAGE attenuates LPS‐induced chronic neuroinflammation in different brain regions. Furthermore, we found that intranasal FPS‐ZM1 administration reduced levels of gliosis markers, RAGE ligands, and α‐synuclein in the substantia nigra pars compacta. Additionally, the treatment also reversed the increase in S100 calcium‐binding protein B (RAGE ligand) in the cerebrospinal fluid and the cognitive‐behavioral deficits promoted by LPS—less time spent in the central zone of the open‐field arena (more time in the lateral zones), decreased total distance traveled, and increased number of freezing episodes. In summary, our study demonstrates the prominent role of RAGE in the maintenance of a chronic neuroinflammatory state triggered by a single episode of systemic inflammation and also points to possible future RAGE‐based therapeutic approaches to treat conditions in which chronic neuroinflammation and increased α‐synuclein levels could play a relevant role, such as in Parkinson's disease. [ABSTRACT FROM AUTHOR]