Intranasal delivery of dexamethasone efficiently controls LPS‐induced murine neuroinflammation

• Published in: Clinical and experimental immunology 2017-12, Vol.190 (3), p.304-314
• Main Authors: Meneses, G., Gevorkian, G., Florentino, A., Bautista, M. A., Espinosa, A., Acero, G., Díaz, G., Fleury, A., Pérez Osorio, I. N., del Rey, A., Fragoso, G., Sciutto, E., Besedovsky, H.
• Format: Article
• Language: English
• Subjects: Administration, Intranasal; Animals; Antigens, Ly - immunology; Brain; Calcium; Calcium-Binding Proteins - immunology; CD11b antigen; CD11b Antigen - immunology; CD45 antigen; Central nervous system; Cerebral Cortex - immunology; Cerebral Cortex - pathology; Dexamethasone; Drug delivery; Glial fibrillary acidic protein; Glial Fibrillary Acidic Protein - immunology; Glucocorticoids; Hippocampus - immunology; Hippocampus - pathology; Immunosuppressive agents; Inflammation; Interleukin-6 - immunology; intranasal route; Intravenous administration; Leukocyte Common Antigens - immunology; Lipopolysaccharides; Lipopolysaccharides - toxicity; LPS; Macrophages; Male; Mice; Microfilament Proteins - immunology; Microglia; Microglia - immunology; Microglia - pathology; Microvasculature; Neurodegenerative diseases; Neurodegenerative Diseases - chemically induced; Neurodegenerative Diseases - drug therapy; Neurodegenerative Diseases - immunology; Neurodegenerative Diseases - pathology; neuroinflammation; Olfactory system; Original; Rodents; Statistical analysis; Steroids
• ISSN: 0009-9104; 1365-2249
• DOI: 10.1111/cei.13018

Summary Neuroinflammation is the hallmark of several infectious and neurodegenerative diseases. Synthetic glucocorticoids (GCs) are the first‐line immunosuppressive drugs used for controlling neuroinflammation. A delayed diffusion of GCs molecules and the high systemic doses required for brain‐specific targeting lead to severe undesirable effects, particularly when lifelong treatment is required. Therefore, there is an urgent need for improving this current therapeutic approach. The intranasal (i.n.) route is being employed increasingly for drug delivery to the brain via the olfactory system. In this study, the i.n. route is compared to the intravenous (i.v.) administration of GCs with respect to their effectiveness in controlling neuroinflammation induced experimentally by systemic lipopolysaccharide (LPS) injection. A statistically significant reduction in interleukin (IL)‐6 levels in the central nervous system (CNS) in the percentage of CD45+/CD11b+/lymphocyte antigen 6 complex locus G6D [Ly6G+ and in glial fibrillary acidic protein (GFAP) immunostaining was observed in mice from the i.n.‐dexamethasone (DX] group compared to control and i.v.‐DX‐treated animals. DX treatment did not modify the percentage of microglia and perivascular macrophages as determined by ionized calcium binding adaptor molecule 1 (Iba1) immunostaining of the cortex and hippocampus. The increased accumulation of DX in brain microvasculature in DX‐i.n.‐treated mice compared with controls and DX‐IV‐treated animals may underlie the higher effectiveness in controlling neuroinflammation. Altogether, these results indicate that IN‐DX administration may offer a more efficient alternative than systemic administration to control neuroinflammation in different neuropathologies. Peripheral LPS administration induces brain inflammation. When administrated by the intranasal route, dexamethasone was more effective in reducing neuroinflammation than when administrated intravenously. This result points the IN route as a more efficient alternative for glucocorticoid administration to control neuroinflammation.