Harpagoside is a natural iridoid glycoside with anti-inflammatory, anticancer, and neuroprotective activities. Harpagoside inhibits NF-κB and AP-1 activation, downregulates iNOS, COX-2, TNF-α, IL-6, and IL-1β, reduces oxidative stress through the Nrf2/HO-1 axis, and inhibits osteoclast differentiation. Harpagoside can be used for research on osteoarthritis, rheumatoid arthritis, chronic pain, and Alzheimer's disease[1-4].
In vitro, treatment of IFNγ/LPS-stimulated THP-1 cells with 5-500μM Harpagoside for 24 hours reduced TNFα secretion[5]. Pretreatment of HepG2 cells with 200μM Harpagoside for 2 hours followed by 10µg/ml LPS treatment for 1 or 6 hours. Harpagoside inhibited COX-2 and iNOS protein expression, blocked NF-κB p65 nuclear translocation, and inhibited IκB-α degradation[6]. Pretreatment of cultured rat mesencephalic neurons with 1µM Harpagoside for 24 hours followed by 10µM 1-Methyl-4-phenylpyridine treatment for 48 hours. Harpagoside reduced TH-positive neuron loss and axon length shortening[7].
In vivo, oral administration of 10mg/kg Harpagoside to DBA/1 arthritic mice every other day until day 42. Harpagoside reduced arthritis clinical scores, alleviated ankle joint inflammation, cartilage destruction, pannus formation, and local bone erosion, decreased serum TNF-α, IL-6, and IL-1β, downregulated RANKL, upregulated OPG, reduced trabecular bone loss in femur, and decreased TRAP-positive osteoclasts[8]. Epidural injection of 100-200μg/kg Harpagoside to lumbar spinal stenosis rats once daily for 4 weeks. Harpagoside reduced ED1+ inflammatory cell infiltration, decreased iNOS, IL-1β, TNF-α, and COX2 expression, upregulated IL-10 and Arg1, improved gait, motor function, ladder walking performance, and mechanical pain threshold[9]. Oral administration of 42mg/kg Harpagoside to C57BL/6 mice once daily for 4 weeks after 4 weekly tail vein injections of 5mg/kg doxorubicin. Harpagoside improved EF and FS values, alleviated myocardial fiber loss and disarray, reduced serum LDH and CK-MB, decreased cardiomyocyte apoptosis, and reduced mtDNA oxidative damage[10].
References:[1] Kaur H, Kumar D, Gauttam VK, et al. Decoding the mechanistic landscape of harpagoside: From molecular targets to translational pharmacology. Fitoterapia. 2026 Jan;188:107029.
[2] Haseeb A, Ansari MY, Haqqi TM. Harpagoside suppresses IL-6 expression in primary human osteoarthritis chondrocytes. J Orthop Res. 2017 Feb;35(2):311-320.
[3] Pérez Gutiérrez RM, Rodríguez-Serrano LM, Laguna-Chimal JF, et al. Geniposide and Harpagoside Functionalized Cerium Oxide Nanoparticles as a Potential Neuroprotective. Int J Mol Sci. 2024 Apr 11;25(8):4262.
[4] Lang J, Xiong Z. Protective effects of harpagoside on mitochondrial functions in rotenone‑induced cell models of Parkinson's disease. Biomed Rep. 2025 Feb 11;22(4):64.
[5] Schopohl P, Grüneberg P, Melzig M.F, et al. The influence of harpagoside and harpagide on TNFα-secretion and cell adhesion molecule mRNA-expression in IFN/LPS-stimulated THP-1 cells. Fitoterapia. 2016;113:148-156.
[6] Huang T, Tran V, Duke R, et al. Harpagoside suppresses lipopolysaccharide-induced iNOS and COX-2 expression through inhibition of NF-kB activation. Journal of Ethnopharmacology. 2006;104(1-2):149-55.
[7] Sun X, Xiong Z, Zhang Y, et al. Harpagoside attenuates MPTP/MPP+ induced dopaminergic neurodegeneration and movement disorder via elevating glial cell line-derived neurotrophic factor. J Neurochem. 2012;120(6):1072-1083.
[8] Kim J-Y, Cheon Y-H, Ahn S-J, et al. Harpagoside attenuates local bone erosion and systemic osteoporosis in collagen-induced arthritis in mice. BMC Complement Med Ther. 2022;22:214.
[9] Hong J.Y, Kim H, Yeo C, et al. Epidural Injection of Harpagoside for the Recovery of Rats with Lumbar Spinal Stenosis. Cells. 2023;12(18):2281.
[10] Li W, Wang X, Liu T, et al. Harpagoside Protects Against Doxorubicin-Induced Cardiotoxicity via P53-Parkin-Mediated Mitophagy. Front Cell Dev Biol. 2022 Feb 10;10:813370.