The brain is one of the earliest organs to be influenced during sepsis. Sepsis-associated encephalopathy (SAE) is frequent, but seldomly recognized and has no testified pharmacological therapy. In this study, we demonstrated that pentamidine, an antiprotozoal drug, is a good candidate since it blocks S100B/RAGE/NF-kappa B signaling pathway. Pentamidine ameliorated cecal ligation and puncture (CLP)-induced brain damage assessed by crystal violet staining and hematoxylin and eosin (H&E) staining. Moreover, pentamidine reduced neuroinflammation in mouse hippocampi. Immunofluorescence and Western blot analysis also showed that pentamidine inhibited CLP-induced gliosis and S100B/RAGE/NF-kappa B pathway activation. Interestingly, it could also attenuate oxidative stress indicated by decreased protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and attenuation of malondialdehyde (MDA) accumulation and superoxide dismutase (SOD) consumption. Thus the S100B/RAGE/NF-kappa B pathway may be crucial in the pathogenesis of SAE and may be a promising pharmacological target to prevent SAE. (C) 2019 Elsevier Inc. All rights reserved.