Scopoletin (Gelseminic acid) is a naturally occurring phenolic coumarin and an acetylcholinesterase (AChE) inhibitor with IC50 of 168.6μM[1]. Scopoletin inhibits AChE and regulates nuclear factor-kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling, thereby altering cholinergic neurotransmission, inflammatory activation, angiogenesis, and melanogenesis[1-4]. Scopoletin is used in research on cholinergic signaling, pigmentation, angiogenesis, autoimmune neuroinflammation, arthritis, urate crystal-induced inflammation, and inflammation-associated anxiety[1-7].
In vitro, Scopoletin (40μg/mL; 72h) increased intracellular melanin, tyrosinase activity, tyrosinase-related protein 1 (TRP-1), microphthalmia-associated transcription factor (MITF), cAMP production, and p38 MAPK phosphorylation in B16F10 melanoma cells[2]. Scopoletin (10μM, 30μM, and 100μM; 24h; 10ng/mL fibroblast growth factor 2) reduced human umbilical vein endothelial cell proliferation, migration, and tubule formation and decreased vascular endothelial growth factor expression, inhibitor of nuclear factor kappa-B kinase alpha phosphorylation, and inhibitor of NF-κB degradation[3]. Scopoletin (100μM; 18h; 100ng/mL lipopolysaccharide) reduced major histocompatibility complex class II, cluster of differentiation 80, cluster of differentiation 86, NF-κB phosphorylation, interleukin-1 beta, and tumor necrosis factor-alpha in mouse bone marrow-derived dendritic cells[4].
In vivo, Scopoletin (50mg/kg; intraperitoneal injection once daily from day 0 to day 20 after immunization) reduced disease scores, spinal-cord inflammatory infiltration, demyelination, dendritic-cell activation, and pathogenic T helper 1/T helper 17 responses in C57BL/6 mice with experimental autoimmune encephalomyelitis[4]. Scopoletin (50mg/kg and 100mg/kg; intraperitoneal injection once daily for 23 days) reduced joint inflammation, cartilage and bone destruction, synovial microvessel density, and angiogenic mediator expression in Sprague-Dawley rats with adjuvant-induced arthritis[5]. Scopoletin (50mg/kg, 100mg/kg, and 200mg/kg; single intraperitoneal injection; 6h) reduced leukocyte infiltration and inflammatory mediator production in the air pouches of ICR mice challenged with monosodium urate crystals[6]. Scopoletin (2mg/kg, 10mg/kg, and 50mg/kg; intraperitoneal injection once daily for 14 days) reduced microglial activation, interleukin-1 beta, interleukin-6, tumor necrosis factor-alpha, NF-κB/MAPK activation, and anxiety-like behavior in male C57BL/6 mice with complete Freund's adjuvant-induced chronic inflammation[7].
References：[1] Rollinger JM, Hornick A, Langer T, Stuppner H, Prast H. Acetylcholinesterase inhibitory activity of scopolin and scopoletin discovered by virtual screening of natural products. J Med Chem. 2004;47(25):6248-6254. doi:10.1021/jm049655r.
[2] Kim DS, Cha SB, Park MC, Park SA, Kim HS, Woo WH, Mun YJ. Scopoletin stimulates melanogenesis via cAMP/PKA pathway and partially p38 activation. Biol Pharm Bull. 2017;40(12):2068-2074. doi:10.1248/bpb.b16-00690.
[3] Pan R, Gao XH, Lu D, Xu XX, Xia YF, Dai Y. Prevention of FGF-2-induced angiogenesis by scopoletin, a coumarin compound isolated from Erycibe obtusifolia Benth, and its mechanism of action. Int Immunopharmacol. 2011;11(12):2007-2016. doi:10.1016/j.intimp.2011.08.012.
[4] Zhang F, Zhang Y, Yang T, Ye ZQ, Tian J, Fang HR, et al. Scopoletin suppresses activation of dendritic cells and pathogenesis of experimental autoimmune encephalomyelitis by inhibiting NF-kappaB signaling. Front Pharmacol. 2019;10:863. doi:10.3389/fphar.2019.00863.
[5] Pan R, Gao XH, Li Y, Xia YF, Dai Y. Anti-arthritic effect of scopoletin, a coumarin compound occurring in Erycibe obtusifolia Benth stems, is associated with decreased angiogenesis in synovium. Fundam Clin Pharmacol. 2010;24(4):477-490. doi:10.1111/j.1472-8206.2009.00784.x.
[6] Yao X, Ding Z, Xia Y, Wei Z, Luo Y, Feleder C, et al. Inhibition of monosodium urate crystal-induced inflammation by scopoletin and underlying mechanisms. Int Immunopharmacol. 2012;14(4):454-462. doi:10.1016/j.intimp.2012.07.024.
[7] Luo L, Sun T, Yang L, Liu A, Liu QQ, Tian QQ, et al. Scopoletin ameliorates anxiety-like behaviors in complete Freund's adjuvant-induced mouse model. Mol Brain. 2020;13(1):15. doi:10.1186/s13041-020-0560-2.