Neurostatin and other O-acetylated gangliosides show anti-neuroinflammatory activity involving the NFκB pathway
| Autor: | Michel Gilbert, Ana Cristina Ojalvo-Sanz, Lorenzo Romero-Ramírez, Marie-France Goneau, Manuel Nieto-Sampedro, Aroa Martínez-Vázquez, Natalia Yanguas-Casás |
|---|---|
| Přispěvatelé: | Ministerio de Economía y Competitividad (España) |
| Rok vydání: | 2019 |
| Předmět: |
Lipopolysaccharides
Male 0301 basic medicine Ceramide Lipopolysaccharide Neurostatin Anti-Inflammatory Agents Organic Anion Transporters microglia neurostatin Toxicology Neuroprotection Glycosphingolipids Cell Line neuroinflammation Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Neuroinflammation Gangliosides medicine Animals Interferon gamma Rats Wistar anti-inflammatory Pharmacology Ganglioside Microglia lipopolysaccharide NF-kappa B gangliosides Rats Cell biology Sialic acid Mice Inbred C57BL Neuroprotective Agents 030104 developmental biology medicine.anatomical_structure chemistry 030220 oncology & carcinogenesis Encephalitis Anti-inflammatory Signal Transduction medicine.drug |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 0041-008X |
| Popis: | In many neuropathologies activated microglia and macrophages cause neurotoxicity and prolong the inflammatory response. We have previously characterized the glycosphingolipid Neurostatin (Nst), which potentially reduces these detrimental mechanisms. Nst, isolated from mammalian brain, is the GD1b ganglioside with O-acetylation of the outer sialic acid residue. Using the enzyme sialate-O-acetyltransferase (SOAT), we obtained several O-acetylated gangliosides and O-propionylated GD1b (PrGD1b). In the present study we investigated the anti-inflammatory effects of these compounds. Nst and other O-acetylated gangliosides reduced nitrite production in microglial cells which were activated with lipopolysaccharide (LPS), but did not affect nitrite production after their stimulation with interferon gamma (IFNγ). Structure-activity relationship analysis showed that Nst was the most active ganglioside as inhibitor of nitrite production. Its ceramide moiety is essential for this, and both, the O-acetylation and the monosaccharide chain are important for the anti-inflammatory activity of the gangliosides. We also found that Nst reduced iNOS, IL-6 and IL-12 transcription in LPS-induced microglia, likely by inhibiting nuclear localization of NFκB. In co-cultures, Nst reduced neuronal cell death caused by LPS-activated microglia. In vivo, Nst diminished microglia activation in a mouse model of acute neuroinflammation. We propose that Nst and other O-acetylated gangliosides are neuroprotective regulators of microglia activity under both physiological and pathological conditions. This work was supported by a grant of Ministry of Economy and Competitiveness, Government of Spain (SAF2012-40126). |
| Databáze: | OpenAIRE |
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