Curcuma longa has traditionally been used as a spice, natural colorant, food preservative, and medicinal plant. It has also been applied in treating various ailments, including dyslipidemia, gastrointestinal disorders, arthritis, and liver diseases. This study aimed to investigate the anti-neuroinflammatory properties of a 50% ethanolic extract of C. longa (CLE) in lipopolysaccharide (LPS)-activated BV2 microglial cells. The Griess assay was used to quantify nitric oxide (NO) production, while prostaglandin E2 (PGE2) and pro-inflammatory cytokines—interleukin 1-beta (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α)—were measured using commercial ELISA kits. Western blot analysis assessed the expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nuclear factor kappa B (NF-κB), mitogen-activated protein kinases (MAPKs), heme oxygenase-1 (HO-1), and nuclear factor erythroid 2-related factor 2 (Nrf2). Pre-treatment with CLE reduced both the production and expression of pro-inflammatory mediators, including NO, PGE2, iNOS, COX-2, and cytokines IL-1β, IL-6, and TNF-α, in LPS-stimulated BV2 cells. CLE also suppressed the activation of NF-κB and the three major MAPK pathways. Furthermore, CLE induced HO-1 expression through Nrf2 activation, and blocking HO-1 reversed CLE’s anti-inflammatory effects. CLE exhibited anti-neuroinflammatory activity in LPS-stimulated microglial cells by inhibiting the production and expression of pro-inflammatory mediators via negative regulation of NF-κB and MAPK pathways. These effects were mediated through the HO-1/Nrf2 signaling axis. Overall, the findings suggest CLE could be a promising candidate for preventing neuroinflammatory conditions, warranting further in vivo studies for efficacy evaluation.
