Hecubine suppresses lipopolysaccharide-stimulated neuroinflammation and oxidative stress by targeting TREM2 and regulating Nrf2/TLR4 signaling in vitro and in vivo

Abstract

Abstract Neuroinflammation and oxidative stress play crucial roles in many neurological diseases of the central nervous system. Targeting key proteins in inflammatory signaling may provide a new therapy for neuroinflammation. Hecubine is an active monoterpene indole alkaloid found in Ervatamia officinalis and the majority of its biological activities have not yet been explored. In the present study, we investigated the effects and mechanism of Hecubine on LPS-mediated neuroinflammation in vivo and in vitro for the first time. The results demonstrated that Hecubine reduced LPS-stimulated inflammatory cytokines overexpression, activated TREM2 expression, as well as suppressed the levels of TLR4-, MyD88-, and NF-κB-related proteins in BV2 microglia cells. Hecubine also exhibited an antioxidative effect, as evidenced by the reduction of ROS production and activation of the Nrf2/HO-1 pathway. Further drug target identification revealed that TREM2 is a primary interacting target of Hecubine. Knockdown of TREM2 mRNA expression significantly abolished Hecubine-induced anti-inflammatory and antioxidative effects via the upregulation of TLR4 signaling and the downregulation of Nrf2 pathway proteins. In vivo, after injection of LPS into the brain of zebrafish larvae, Hecubine administration obviously rescued behavioral deficits, inhibited the expression of pro-inflammatory cytokines, and prevented oxidative stress by activating TREM2. Taken together, Hecubine directly targets TREM2 to reduce neuroinflammation and oxidative stress and serves as a potential therapeutic agent for the treatment of neural inflammation-associated CNS diseases.