Neurostatin and other O-acetylated gangliosides show anti-neuroinflammatory activity involving the NFκB pathway

• Published in: Toxicology and applied pharmacology 2019-08, Vol.377, p.114627, Article 114627
• Main Authors: Yanguas-Casás, Natalia, Ojalvo-Sanz, Ana Cristina, Martínez-Vázquez, Aroa, Goneau, Marie-France, Gilbert, Michel, Nieto-Sampedro, Manuel, Romero-Ramírez, Lorenzo
• Format: Article
• Language: English
• Subjects: Animals; Anti-inflammatory; Anti-Inflammatory Agents - pharmacology; Cell Line; Encephalitis - prevention & control; Gangliosides; Gangliosides - pharmacology; Glycosphingolipids - pharmacology; Lipopolysaccharide; Lipopolysaccharides - pharmacology; Male; Mice; Mice, Inbred C57BL; Microglia; Microglia - drug effects; Neuroinflammation; Neuroprotective Agents - pharmacology; Neurostatin; NF-kappa B - drug effects; Organic Anion Transporters - metabolism; Rats; Rats, Wistar; Signal Transduction - drug effects
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2019.114627

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. •Neurostatin reduces LPS-induced activation of microglial cells in vivo and in vitro.•The O-acetylation and the ceramide are essential for its anti-inflammatory effect.•Neurostatin reduces LPS-activated microglia induced neuronal cell death.•Nst diminishes neuronal cell death caused by LPS-activated microglia.•Nst and other gangliosides might normalize the pro-inflammatory microglia.