A natural small molecule aspidosperma-type alkaloid, hecubine, as a new TREM2 activator for alleviating lipopolysaccharide-induced neuroinflammation in vitro and in vivo

• DOI: 10.1016/j.redox.2024.103057
• Publication Date: 2024-01-24T03:06:36Z
• Authors: Lin Li; Yu-Lin He; Nan Xu; Xiu-Fen Wang; Bing Song; Ben-Qin Tang; Simon Ming-Yuen Lee
• Keywords: TREM2; Proinflammatory cytokine

Neuroinflammation and oxidative stress play a crucial role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease. The triggering receptor expressed on myeloid cells 2 (TREM2), highly by microglia central nervous system (CNS), can modulate neuroinflammatory responses. Currently, there are no approved drugs specifically targeting TREM2 for CNS diseases. Aspidosperma alkaloids have shown potential as anti-inflammatory neuroprotective agents. This study aimed to elucidate therapeutic effect Hecubine, natural aspidosperma-type alkaloid, activator lipopolysaccharide (LPS)-stimulated neuroinflammation vitro vivo models. In this study, molecular docking cellular thermal shift assay (CTSA) were employed investigate interaction between Hecubine TREM2. Enzyme-linked immunosorbent (ELISA), quantitative PCR, immunofluorescence, Western blotting, shRNA gene knockdown used assess anti-neuroinflammatory antioxidant effects microglial zebrafish. Our results revealed that directly interacted with TREM2, leading its activation. Knockdown mRNA expression significantly abolished LPS-stimulated proinflammatory mediators (NO, TNF-α, IL-6, IL-1β) cells. Furthermore, upregulated Nrf2 levels while downregulating TLR4 signaling both vitro. Silencing downregulated pathways, mimicking further supporting drug target which inhibits neuroinflammation. conclusion, is first identify small molecule, namely mediate anti-neuroinflammation anti-oxidative effects, serves agent treatment neural inflammation-associated