Anti-Neuroinflammatory Effects of a Novel Bile Acid Derivative

• Published in: International journal of molecular sciences Vol. 25; no. 13; p. 7136
• Main Authors: Bjedov, Srđan, Stegnjaić, Goran, Stanisavljević, Suzana, Lazarević, Milica, Pilipović, Ivan, Sakač, Marija, Miljković, Đorđe
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 28.06.2024
• Subjects: Acids; Animals; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Antigens; Bile; Bile Acids and Salts - metabolism; Bile Acids and Salts - pharmacology; cytokine; Cytokines; Cytokines - metabolism; Dendritic cells; Disease; Enzymes; Humans; Lymphatic system; Lymphocytes; Mice; microglia; Microglia - drug effects; Microglia - metabolism; Multiple sclerosis; myeloid cells; Neurodegeneration; Neuroinflammatory Diseases - drug therapy; NF-E2-Related Factor 2 - metabolism; Nitric Oxide - metabolism; Nrf2; Nrf2 activator; Pathogenesis; Signal Transduction - drug effects; Spleen; T cells; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Tumor necrosis factor-TNF; cytokine; Nrf2 activator; myeloid cells; T cells; Nrf2; microglia
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25137136

In the search for novel potent immunomodulatory nuclear factor-erythroid 2 related factor 2 (Nrf2) activators, a derivative of cholic bile acid, SB140, was synthesized. The synthesis of SB140 aimed to increase the electrophilic functionality of the compound, enhancing its ability to activate Nrf2. Effects of SB140 on microglial cells, myeloid-derived cells (MDC), and T cells were explored in the context of (central nervous system) CNS autoimmunity. SB140 potently activated Nrf2 signaling in MDC and microglia. It was efficient in reducing the ability of microglial cells to produce inflammatory nitric oxide, interleukin (IL)-6, and tumor necrosis factor (TNF). Also, SB140 reduced the proliferation of encephalitogenic T cells and the production of their effector cytokines: IL-17 and interferon (IFN)-γ. On the contrary, the effects of SB140 on anti-inflammatory IL-10 production in microglial and encephalitogenic T cells were limited or absent. These results show that SB140 is a potent Nrf2 activator, as well as an immunomodulatory compound. Thus, further research on the application of SB140 in the treatment of neuroinflammatory diseases is warranted. Animal models of multiple sclerosis and other inflammatory neurological disorders will be a suitable choice for such studies.