Sapropterin as a Drug-Repurposing Candidate through the Anti-inflammatory Pathway with Microvascular Improvement in a Rat Model of Hemorrhoids
Keywords:
Hemorrhoid, Inflammation, sapropterin, COX-2, IL-10
Abstract
Hemorrhoids result from increased intra-abdominal pressure that triggers inflammation and oxidative stress within the hemorrhoidal plexus. The condition causes symptoms such as pain, itching, rectal bleeding, and prolapse, which substantially impair quality of life. Persistent inflammatory signaling pathways contribute to recurrence, highlighting the need for novel therapeutic strategies. Cyclooxygenase-2 (COX-2) plays a pivotal role in propagating inflammation and tissue injury, whereas interleukin-10 (IL-10) functions as a key anti-inflammatory cytokine. Sapropterin, a synthetic tetrahydrobiopterin (BH4) analogue, has been proposed to exert anti-inflammatory effects by modulating nitric oxide pathways and cytokine expression. This study aimed to evaluate the efficacy of sapropterin in reducing inflammation and restoring vascular integrity in a rat model of hemorrhoids.
Male Sprague-Dawley rats (200–250 g) were divided into five groups: normal control, negative control (hemorrhoid-induced), positive control (aspirin), and two sapropterin-treated groups (0.3 and 0.6 mg/kg, orally for seven days). Hemorrhoids were induced using 6% croton oil. Serum IL-10 levels were quantified via ELISA, while anorectal tissues were analyzed for IL-10 and COX-2 gene expression using qRT-PCR and histopathological examination. Statistical analysis was performed using One-Way ANOVA followed by Tukey’s test.
Sapropterin at 0.6 mg/kg significantly increased IL-10 expression and reduced COX-2 compared with the negative control group. Histopathological analysis revealed decreased leukocyte infiltration and improved microvascular architecture. These findings demonstrate that sapropterin confers anti-inflammatory and microvascular-protective effects in hemorrhoid-induced rats, suggesting its potential as a repurposed therapeutic candidate for managing hemorrhoid-related inflammation.
References
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Porwal, A., Kundu, G., Bhagwat, G., & Butti, R. (2021). Herbal medicine AnoSpray suppresses proinflammatory cytokines COX 2 and RANTES in the management of hemorrhoids, acute anal fissures and perineal wounds. Experimental and Therapeutic Medicine, 23(1), 86. https://doi.org/10.3892/etm.2021.11009
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Serra, R., Gallelli, L., Grande, R., Amato, B., De Caridi, G., Sammarco, G., Ferrari, F., Butrico, L., Gallo, G., Rizzuto, A., De Franciscis, S., & Sacco, R. (2016). Hemorrhoids and matrix metalloproteinases: A multicenter study on the predictive role of biomarkers. Surgery, 159(2), 487–494. https://doi.org/10.1016/J.SURG.2015.07.003
Traeger, R. S., Woodcock, J., Tan, S., Shi, Z., & Vasquez-Vivar, J. (2025). Tetrahydrobiopterin as a rheostat of cell resistance to oxidant injury. Redox Biology, 79, 103447. https://doi.org/10.1016/j.redox.2024.103447
Villaume, W. A. (2022). Marginal BH4 deficiencies, iNOS, and self-perpetuating oxidative stress in post-acute sequelae of Covid-19. Medical Hypotheses, 163, 110842. https://doi.org/10.1016/j.mehy.2022.110842
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Azeemuddin, M., Viswanatha, G. L., Rafiq, M., Thippeswamy, A. H., Baig, M. R., Kavya, K. J., Patki, P. S., & Shyam, R. (2014). An Improved Experimental Model of Hemorrhoids in Rats: Evaluation of Antihemorrhoidal Activity of an Herbal Formulation. ISRN Pharmacology, 2014, 1–7. https://doi.org/10.1155/2014/530931
Boyd-Mutinga, F. A., Topaz, G. R., Silva, C. L., Berger, N. J., Egbujie, K., De Rodriguez, S. F., Iyungu, C., Sosa, H. M., Begay, S. C., & Stieglitz, K. A. (2020). Characterization of Predicted Binding Modes of Acetylsalicylic Acid (Aspirin) to the COX-2 Target. The FASEB Journal, 34(S1), 1. https://doi.org/https://doi.org/10.1096/fasebj.2020.34.s1.05631
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Chuaiphichai, S., Rashbrook, V. S., Hale, A. B., Trelfa, L., Patel, J., McNeill, E., Lygate, C. A., Channon, K. M., & Douglas, G. (2018). Endothelial Cell Tetrahydrobiopterin Modulates Sensitivity to Ang (Angiotensin) II–Induced Vascular Remodeling, Blood Pressure, and Abdominal Aortic Aneurysm. Hypertension, 72(1), 128–138. https://doi.org/10.1161/HYPERTENSIONAHA.118.11144
De Marco, S., & Tiso, D. (2021). Lifestyle and Risk Factors in Hemorrhoidal Disease. Frontiers in Surgery, 8. https://doi.org/10.3389/fsurg.2021.729166
Devi, V., Deswal, G., Dass, R., Chopra, B., Kriplani, P., Grewal, A. S., & Dhingra, A. K. (2023). Hemorrhoid Disease: A Review on Treatment, Clinical Research and Patent Data. Infectious Disorders - Drug Targets, 23(6). https://doi.org/10.2174/1871526523666230427115436
Dubey, T., Bhanukiran, K., Prasad, S. K., & Hemalatha, S. (2023). Optimization of Extraction Process and Anti-Hemorrhoidal Activity of Blumea lacera (Burm.f.) DC. Leaves in Croton Oil-induced Hemorrhoid Model. Pharmacognosy Magazine, 19(3), 709–719. https://doi.org/10.1177/09731296231170936
Engineer, A., Lim, Y. J., Lu, X., Kim, M. Y., Norozi, K., & Feng, Q. (2020). Sapropterin reduces coronary artery malformation in offspring of pregestational diabetes mice. Nitric Oxide, 94, 9–18. https://doi.org/10.1016/j.niox.2019.10.002
Feng, Y., Feng, Y., Gu, L., Mo, W., Wang, X., Song, B., Hong, M., Geng, F., Huang, P., Yang, H., Zhu, W., Jiao, Y., Zhang, Q., Ding, W.-Q., Cao, J., & Zhang, S. (2024). Tetrahydrobiopterin metabolism attenuates ROS generation and radiosensitivity through LDHA S-nitrosylation: novel insight into radiogenic lung injury. Experimental & Molecular Medicine, 56(5), 1107–1122. https://doi.org/10.1038/s12276-024-01208-z
Fišere, I., Groma, V., Svirskis, Š., Strautmane, E., & Gardovskis, A. (2023). Evaluation of Clinical Manifestations of Hemorrhoidal Disease, Carried Out Surgeries and Prolapsed Anorectal Tissues: Associations with ABO Blood Groups of Patients. Journal of Clinical Medicine, 12(15). https://doi.org/10.3390/jcm12155119
Gallo, G., Martellucci, J., Sturiale, A., Clerico, G., Milito, G., Marino, F., Cocorullo, G., Giordano, P., Mistrangelo, M., & Trompetto, M. (2020). Consensus statement of the Italian society of colorectal surgery (SICCR): management and treatment of hemorrhoidal disease. Techniques in Coloproctology, 24(2), 145–164. https://doi.org/10.1007/s10151-020-02149-1
Hernandez-Navarro, I., Botana, L., Diez-Mata, J., Tesoro, L., Jimenez-Guirado, B., Gonzalez-Cucharero, C., Alcharani, N., Zamorano, J. L., Saura, M., & Zaragoza, C. (2024). Replicative Endothelial Cell Senescence May Lead to Endothelial Dysfunction by Increasing the BH2/BH4 Ratio Induced by Oxidative Stress, Reducing BH4 Availability, and Decreasing the Expression of eNOS. International Journal of Molecular Sciences, 25(18), 9890. https://doi.org/10.3390/ijms25189890
Hu, P., Luo, S., Qu, G., Luo, Q., Tian, Y., Huang, K., & Sun, T. (2023). Identification and validation of feature genes associated with M1 macrophages in preeclampsia. Aging, 15(23), 13822–13839. https://doi.org/10.18632/aging.205264
Janaszak-Jasiecka, A., Płoska, A., Wierońska, J. M., Dobrucki, L. W., & Kalinowski, L. (2023). Endothelial dysfunction due to eNOS uncoupling: molecular mechanisms as potential therapeutic targets. Cellular & Molecular Biology Letters, 28(1), 21. https://doi.org/10.1186/s11658-023-00423-2
Kang, S. Il. (2025). Latest Research Trends on the Management of Hemorrhoids. Journal of the Anus, Rectum and Colon, 9(2), 2024–2090. https://doi.org/10.23922/jarc.2024-090
Ke, M., Huang, S., Lin, H., Xu, Z., Li, X., Li, Z., Chen, F., & Wu, H. (2023). Establishment and study of a rat internal haemorrhoid model. Scientific Reports, 13(1), 21385. https://doi.org/10.1038/s41598-023-48677-2
Kelly, K. A., Heaps, C. L., Wu, G., Labhasetwar, V., & Meininger, C. J. (2024). Nanoparticle-mediated delivery of tetrahydrobiopterin restores endothelial function in diabetic rats. Nitric Oxide, 148, 13–22. https://doi.org/10.1016/j.niox.2024.04.009
Kibret, A. A., Oumer, M., & Moges, A. M. (2021). Prevalence and associated factors of hemorrhoids among adult patients visiting the surgical outpatient department in the University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia. PLOS ONE, 16(4), e0249736. https://doi.org/10.1371/journal.pone.0249736
Li, H., Förstermann, U., Xia, N., Kuntic, M., Münzel, T., & Daiber, A. (2025). Pharmacological targeting of endothelial nitric oxide synthase dysfunction and nitric oxide replacement therapy. Free Radical Biology and Medicine, 237, 455–472. https://doi.org/10.1016/j.freeradbiomed.2025.06.009
Liang, Y., Ren, T., Li, R., Yu, Z., Wang, Y., Zhang, X., Qin, Z., Li, J., Hu, J., & Luo, C. (2024). Natural Products with Potential Effects on Hemorrhoids: A Review. In Molecules (Vol. 29, Issue 11). Multidisciplinary Digital Publishing Institute (MDPI). https://doi.org/10.3390/molecules29112673
Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods, 25(4), 402–408. https://doi.org/10.1006/meth.2001.1262
Magnusson, R., Rundquist, O., Kim, M. J., Hellberg, S., Na, C. H., Benson, M., Gomez-Cabrero, D., Kockum, I., Tegnér, J. N., Piehl, F., Jagodic, M., Mellergård, J., Altafini, C., Ernerudh, J., Jenmalm, M. C., Nestor, C. E., Kim, M.-S., & Gustafsson, M. (2022). RNA-sequencing and mass-spectrometry proteomic time-series analysis of T-cell differentiation identified multiple splice variants models that predicted validated protein biomarkers in inflammatory diseases. Frontiers in Molecular Biosciences, 9. https://doi.org/10.3389/fmolb.2022.916128
Makita, S., Takatori, H., & Nakajima, H. (2021). Post-Transcriptional Regulation of Immune Responses and Inflammatory Diseases by RNA-Binding ZFP36 Family Proteins. Frontiers in Immunology, 12. https://doi.org/10.3389/fimmu.2021.711633
Parol, B., Sas, O., Mazurek, M., Data, K., Wozniak, S., & Domagala, Z. (2025). How Can Molecules Induce Hemorrhoids? The Role of Genetics and Epigenetics in Hemorrhoidal Disease. International Journal of Molecular Sciences, 26(19), 9394. https://doi.org/10.3390/ijms26199394
Porwal, A., Kundu, G., Bhagwat, G., & Butti, R. (2021). Herbal medicine AnoSpray suppresses proinflammatory cytokines COX 2 and RANTES in the management of hemorrhoids, acute anal fissures and perineal wounds. Experimental and Therapeutic Medicine, 23(1), 86. https://doi.org/10.3892/etm.2021.11009
Ramadan, Y. N., Kamel, A. M., Medhat, M. A., & Hetta, H. F. (2024). MicroRNA signatures in the pathogenesis and therapy of inflammatory bowel disease. Clinical and Experimental Medicine, 24(1), 217. https://doi.org/10.1007/s10238-024-01476-z
Riwanto I, Nugroho Agung Eriawan, Susilaningsih Neni, Prajoko Wisnu Yan, Budiono Parish, Prasetya Adi Sigit, & Azhar Abu. (2020). Antioxidant and Anti-inflammatory effectof Graptophyllumpictum (L.) Griff extractStudy on SOD and COX-2 serum of experimental hemorrhoids. Medica Hospitalia Jpurnal of Clinical Medicine, 7(2), 422–426. https://doi.org/https://doi.org/10.36408/mhjcm.v7i2.515
Saraiva, M., Vieira, P., & O’Garra, A. (2020). Biology and therapeutic potential of interleukin-10. Journal of Experimental Medicine, 217(1). https://doi.org/10.1084/jem.20190418
Serra, R., Gallelli, L., Grande, R., Amato, B., De Caridi, G., Sammarco, G., Ferrari, F., Butrico, L., Gallo, G., Rizzuto, A., De Franciscis, S., & Sacco, R. (2016). Hemorrhoids and matrix metalloproteinases: A multicenter study on the predictive role of biomarkers. Surgery, 159(2), 487–494. https://doi.org/10.1016/J.SURG.2015.07.003
Traeger, R. S., Woodcock, J., Tan, S., Shi, Z., & Vasquez-Vivar, J. (2025). Tetrahydrobiopterin as a rheostat of cell resistance to oxidant injury. Redox Biology, 79, 103447. https://doi.org/10.1016/j.redox.2024.103447
Villaume, W. A. (2022). Marginal BH4 deficiencies, iNOS, and self-perpetuating oxidative stress in post-acute sequelae of Covid-19. Medical Hypotheses, 163, 110842. https://doi.org/10.1016/j.mehy.2022.110842
Zhong, J., Yu, X., & Lin, Z. (2024). Safety assessment of sapropterin dihydrochloride: real-world adverse event analysis based on the FDA adverse event reporting system (FAERS). Frontiers in Pharmacology, 15. https://doi.org/10.3389/fphar.2024.1486597
Published
2026-04-29
How to Cite
Hamidy, M. Y., Ismawati Ismawati, Wirawan Adikusuma, Darmawi Darmawi, Alauddin Syaifulanwar, & Annisa Abdi Ghifari. (2026). Sapropterin as a Drug-Repurposing Candidate through the Anti-inflammatory Pathway with Microvascular Improvement in a Rat Model of Hemorrhoids. Indonesian Journal of Pharmacy. https://doi.org/10.22146/ijp.25779
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