Sains Malaysiana 54(2)(2025): 557-567

http://doi.org/10.17576/jsm-2025-5402-20

Curcumin Improves the Expression of Phospholiphase C and Transient Receptor Potential Vanilloid Type 1 on Neuronal Myometrium in Dysmenorrhea Model

(Kurkumin Memperbaiki Ekspresi Fosfolipase C dan Potensi Reseptor Fana Vanilloid Jenis 1 pada Neuron Miometrium dalam Model Dismenorea)

MUKHOIROTIN^1,2, ABDUL KHAIRUL RIZKI PURBA^3,4,*, BAMBANG PURWANTO⁵, ERNAWATI⁶, HAMIMATUS ZAINIYAH^1,7 & LINA PATRICIA GUTJAHR⁸

¹Doctoral Program of Medical Science, Faculty of Medicine, Universitas Airlangga, Indonesia
²Department of Nursing, Faculty of Health Science, Universitas Pesantren Tinggi Darul Ulum (Unipdu), Indonesia
³Department of Pharmacology, Faculty of Medicine, Universitas Airlangga, Indonesia
⁴Department of Health Science, University Medical Center Groningen, University of Groningen, The Netherlands
⁵Department of Physiology and Medical Biochemistry, Faculty of Medicine, Universitas Airlangga, Indonesia
⁶Department of Obstetric Gynecology, Faculty of Medicine, Universitas Airlangga, Indonesia
⁷Institute of Health Science, Ngudia Husada, Bangkalan, Madura, Indonesia
⁸Faculty of Medicine, Saarland University, Saarbrücken, Germany

Diserahkan: 7 Ogos 2024/Diterima: 20 November 2024

Abstract

The pathogenesis of primary dysmenorrhea is closely related to increased expression of phospholipase C (PLC) and transient receptor potential vanilloid 1 (TRPV1) in myometrial nerve cells. Curcumin has traditionally been used to reduce the pain associated with dysmenorrhea. To date, the effect of curcumin on the expression of PLC and TRPV1 in myometrial pain sensitization has not been studied. This study aimed to determine the impact of curcumin on the expression of PLC and TRPV1 in the myometrial nerves of a primary dysmenorrhea model. The study involved a randomized post-test control group design using non-pregnant female Balb/c mice as a model of primary dysmenorrhea induced by estradiol benzoate and oxytocin. Thirty-five mice that met the inclusion criteria were divided into five groups: sham group (SG), receiving placebo; ibuprofen group (IG) receiving ibuprofen 100 mg/kg; Cur100 receiving curcumin 100 mg/kg; Cur200 receiving curcumin 200 mg/kg; and Cur400 receiving curcumin 400 mg/kg. Each drug was administered orally twice daily for 7 days. Finally, oxytocin was administered to induce a writhing response in the mice. PLC and TRPV1 expression were examined using double immunofluorescence staining. Data were analyzed using a one-way analysis of variance and Tukey’s test. Curcumin significantly lowered PLC and TRPV1 expressions in the primary dysmenorrhea model compared to those in the SG (p<0.05). The best effect was observed in the Cur400 group with the PLC expression at 27.31+7.42 (p<0.001), and TRPV1 expression at 33.21±9.99 (p<0.001). In a primary dysmenorrhea model, Curcumin effectively improves PLC and TRPV1 expression in myometrial nerves.

Keywords: Curcumin; dysmenorrhea; PLC; reproductive health; TRPV1

Abstrak

Patogenesis dismenorea primer berkait rapat dengan peningkatan ekspresi phospholipase C (PLC) dan potensi reseptor fana vanilloid Jenis 1 (TRPV1) dalam sel saraf miometrium. Kurkumin secara tradisinya telah digunakan untuk mengurangkan kesakitan yang berkaitan dengan dismenorea. Sehingga kini, kesan kurkumin pada ekspresi PLC dan TRPV1 dalam pemekaan sakit miometrium belum dikaji. Penyelidikan ini bertujuan untuk menentukan kesan kurkumin terhadap ekspresi PLC dan TRPV1 dalam saraf miometrium model dismenorea primer. Penyelidikan ini melibatkan reka bentuk kumpulan kawalan ujian pasca rawak menggunakan tikus Balb/c betina tidak hamil sebagai model dismenorea primer yang disebabkan oleh estradiol benzoat dan oksitosin. Tiga puluh lima tikus yang memenuhi kriteria kemasukan dibahagikan kepada lima kumpulan: kumpulan sham (SG), menerima plasebo; kumpulan ibuprofen (IG) menerima ibuprofen 100 mg/kg, Cur100 menerima curcumin 100 mg/kg, Cur200 menerima curcumin 200 mg/kg dan Cur400 menerima curcumin 400 mg/kg. Setiap ubat diberikan secara oral dua kali sehari selama 7 hari. Akhirnya, oksitosin diberikan untuk mendorong tindak balas menggeliat pada tikus. Ekspresi PLC dan TRPV1 diperiksa menggunakan pewarnaan imunofluoresensi berganda. Data dianalisis menggunakananalisis varian sehalaand ujian Tukey. Kurkumin menurunkan ekspresi PLC dan TRPV1 dengan ketara dalam model dismenorea primer berbanding dengan model SG (p<0.05). Kesan terbaik diperhatikan dalam kumpulan Cur400 dengan ekspresi PLC pada 27.31 + 7.42 (p<0.001), dan ungkapan TRPV1 pada 33.21 ± 9.99 (p<0.001). Dalam model dismenorea primer, kurkumin berkesan meningkatkan ekspresi PLC dan TRPV1 dalam saraf miometrium.

Kata kunci: Dismenorea; kesihatan reproduktif; kurkumin; PLC; TRPV1

RUJUKAN

Bahrami, A., Zarban, A., Rezapour, H., Agha Amini Fashami, A. & Ferns, G.A. 2021. Effects of curcumin on menstrual pattern, premenstrual syndrome, and dysmenorrhea: A triple‐blind, placebo‐controlled clinical trial. Phytotherapy Research 35(12): 6954-6962. https://doi.org/10.1002/ptr.7314

Bakhsh, H., Algenaimi, E., Aldhuwayhi, R. & AboWadaan, M. 2022. Prevalence of dysmenorrhea among reproductive age group in Saudi Women. BMC Women’s Health 22(1): 1-14. https://doi.org/10.1186/s12905-022-01654-9

Barcikowska, Z., Rajkowska-Labon, E., Grzybowska, M.E., Hansdorfer-Korzon, R. & Zorena, K. 2020. Inflammatory markers in dysmenorrhea and therapeutic options. International Journal of Environmental Research and Public Health 17(4): 1191. https://doi.org/10.3390/ijerph17041191

Bill, C.A. & Vines, C.M. 2020. Phospholipase C. Advances in Experimental Medicine and Biology 1131: 215-242. https://doi.org/10.1007/978-3-030-12457-1_9.

Çinar, G.N., Akbayrak, T., Gürşen, C., Baran, E., Üzelpasacı, E., Nakip, G., Bozdağ, G., Beksaç, M.S. & Özgül, S. 2021. Factors related to primary dysmenorrhea in Turkish women: A multiple multinomial logistic regression analysis. Reproductive Sciences 28(2): 381-392. https://doi.org/10.1007/s43032-020-00289-1

Dasuni Wasana, P.W., Hasriadi, Muangnoi, C., Vajragupta, O., Rojsitthisak, P., Rojsitthisak, P. & Towiwat, P. 2022. Curcumin and metformin synergistically modulate peripheral and central immune mechanisms of pain. Scientific Reports 12: 9713. https://doi.org/10.1038/s41598-022-13647-7

Dewi, F.R.P., Tambunan, U.V.D., Bari, P.A., Farid, M.A., Anjani, N.A., Wahyuningsih, S.P.A., Saik, A.Y.H., Keong, Y.Y., Lim, V., Tan, W.N. & Alshawsh, M.A.M. 2024. Formation of inclusion complex of curcumin and tetrahydrocurcumin prevents angiogenesis by inhibiting VEGF activity: An in-silico study. Sains Malaysiana 53(3): 653-665. https://doi.org/10.17576/jsm-2024-5303-13

Elokely, K., Velisetty, P., Delemotte, L., Palovcak, E., Klein, M.L., Rohacs, T. & Carnevale, V. 2016. Understanding TRPV1 activation by ligands: Insights from the binding modes of capsaicin and resiniferatoxin. Proceedings of the National Academy of Sciences of the United States of America 113(2): E137-E145. https://doi.org/10.1073/pnas.1517288113

Esan, D.T., Ariyo, S.A., Akinlolu, E.F., Akingbade, O., Olabisi, O.I., Olawade, D.B., Bamigboye, T.O. & Ogunfowokan, A.A. 2024. Prevalence of dysmenorrhea and its effect on the quality of life of female undergraduate students in Nigeria. Journal of Endometriosis and Uterine Disorders 5: 100059. https://doi.org/10.1016/j.jeud.2024.100059

Fattah, S.A., Waly, H., El-enein, A.A., Kamel, A. & Labib, H. 2020. Mesenchymal stem cells versus curcumin in enhancing the alterations in the cerebellar cortex of streptozocin-induced diabetic albino rats. The role of GFAP, PLC and α-synuclein. Journal of Chemical Neuroanatomy 109: 101842. https://doi.org/10.1016/j.jchemneu.2020.101842

Harel, Z. 2012. Dysmenorrhea in adolescents and young adults: An update on pharmacological treatments and management strategies. Expert Opinion on Pharmacotherapy 13(15): 2157-2170. https://doi.org/10.1517/14656566.2012.725045

HelloBio. 2022. Signaling Pathways in Pain. https://hellobio.com/media/pdf/Technical-resource/Signaling pathways in pain.pdf

Hillard, P.J.A. 2006. Consultation with the specialist: Dysmenorrhea. Pediatrics in Review 27(2): 64-71. https://doi.org/10.1542/pir.27-2-64

Hong, F., He, G., Zhang, M., Yu, B. & Chai, C. 2022. The establishment of a mouse model of recurrent primary dysmenorrhea. International Journal of Molecular Sciences 23(11): 6128. https://doi.org/10.3390/ijms23116128

Horvat, M., Pavan Jukić, D., Marinović, L., Bursać, D., Ribić, R., Neuberg, M. & Bursać, D. 2023. Prevalence of primary dysmenorrhoea and its impact on academic performance among Croatian students during the COVID-19 pandemic. Obstetrics and Gynecology International 2023: 2953762. https://doi.org/10.1155/2023/2953762

Hu, Z., Tang, L., Chen, L., Kaminga, A.C. & Xu, H. 2020. Prevalence and risk factors associated with primary dysmenorrhea among Chinese female university students: A cross-sectional study. Journal of Pediatric and Adolescent Gynecology 33(1): 15-22. https://doi.org/10.1016/j.jpag.2019.09.004

Jara-Oseguera, A., Simon, S. & Rosenbaum, T. 2010. TRPV1: On the road to pain relief. Current Molecular Pharmacology 1(3): 255-269. https://doi.org/10.2174/1874467210801030255

Kadamur, G. & Ross, E.M. 2013. Mammalian phospholipase C. Annual Review of Physiology 75: 127-154. https://doi.org/10.1146/annurev-physiol-030212-183750

Karout, S., Soubra, L., Rahme, D., Karout, L., Khojah, H.M.J. & Itani, R. 2021. Prevalence, risk factors, and management practices of primary dysmenorrhea among young females. BMC Women’s Health 21: 392. https://doi.org/10.1186/s12905-021-01532-w

Kaur, K., Al-Khazaleh, A.K., Bhuyan, D.J., Li, F. & Li, C.G. 2024. A review of recent curcumin analogues and their antioxidant, anti-inflammatory, and anticancer activities. Antioxidants 13(9): 1092. https://doi.org/10.3390/antiox13091092

Khayat, S., Fanaei, H., Kheirkhah, M., Moghadam, Z.B., Kasaeian, A. & Javadimehr, M. 2015. Curcumin attenuates severity of premenstrual syndrome symptoms: A randomized, double-blind, placebo-controlled trial. Complementary Therapies in Medicine 25(3): 318-324. https://doi.org/10.1016/j.ctim.2015.04.001

Kumar, T.P., Antony, S., Gireesh, G., George, N. & Paulose, C.S. 2010. Curcumin modulates dopaminergic receptor, CREB and phospholipase c gene expression in the cerebral cortex and cerebellum of streptozotocin induced diabetic rats. Journal of Biomedical Science 17(1): 43. https://doi.org/10.1186/1423-0127-17-43

Kwon, D.H., Zhang, F., Suo, Y., Bouvette, J., Borgnia, M.J. & Lee, S.Y. 2021. Heat-dependent opening of TRPV1 in the presence of capsaicin. Nature Structural and Molecular Biology 28(7): 554-563. https://doi.org/10.1038/s41594-021-00616-3

Lee, J.Y., Shin, T.J., Choi, J.M., Seo, K.S., Kim, H.J., Yoon, T.G., Lee, Y.S., Han, H., Chung, H.J., Oh, Y., Jung, S.J. & Shin, K.J. 2013. Antinociceptive curcuminoid, KMS4034, effects on inflammatory and neuropathic pain likely via modulating TRPV1 in mice. British Journal of Anaesthesia 111(4): 667-672. https://doi.org/10.1093/bja/aet176

Lee, S.E., Park, H.R., Jeon, S., Han, D. & Park, Y.S. 2020. Curcumin attenuates acrolein-induced cox-2 expression and prostaglandin production in human umbilical vein endothelial cells. Journal of Lipid and Atherosclerosis 9(1): 184-194. https://doi.org/10.12997/jla.2020.9.1.184

Liu, C., Li, X., Zhou, C., Liang, Y., Zhang, X., Liu, Y., Zhao, Z. & Ma, X. 2022. Effects of ginger-partitioned moxibustion on the expression levels of PGF2α, E2, P, and mRNAs of PGF2αR and E2R in rats with primary dysmenorrhea due to cold-dampness stagnation. Journal of Acupuncture and Tuina Science 20(2): 104-110. https://doi.org/10.1007/s11726-022-1301-0

Mammo, M., Alemayehu, M. & Ambaw, G. 2022. Prevalence of primary dysmenorrhea, its intensity and associated factors among female students at high schools of Wolaita Zone, Southern Ethiopia: Cross-sectional study design. International Journal of Women’s Health 14: 1569-1577. https://doi.org/10.2147/IJWH.S384275

Marjoribanks, J., Ro, A., Farquhar, C. & Proctor, M. 2015. Nonsteroidal anti-inflammatory drugs for dysmenorrhoea (Review). Cochrane Database of Systematic Reviews 2015(7): CD001751. . https://doi.org/10.1002/14651858.CD001751.pub3.www.cochranelibrary.com

Menon, V.P. & Sudheer, A.R. 2007. Antioxidant and anti-inflammatory properties of curcumin. Advances in Experimental Medicine and Biology 595: 105-125. https://doi.org/10.1007/978-0-387-46401-5_3

Mesele, T.T., Dheresa, M., Oljira, L., Wakwoya, E.B. & Gemeda, G.M. 2022. Prevalence of dysmenorrhea and associated factors among Haramaya university students, Eastern Ethiopia. International Journal of Women’s Health 14: 517-527. https://doi.org/10.2147/IJWH.S333447

Moriyuki, K., Sekiguchi, F., Matsubara, K., Nishikawa, H. & Kawabata, A. 2010. Curcumin inhibits the proteinase-activated receptor-2-triggered prostaglandin E2 production by suppressing cyclooxygenase-2 upregulation and Akt-dependent activation of nuclear factor-κB in human lung epithelial cells. Journal of Pharmacological Sciences 114(2): 225-229. https://doi.org/10.1254/jphs.10126SC

Nalli, M., Ortar, G., Schiano Moriello, A., Di Marzo, V. & De Petrocellis, L. 2017. Effects of curcumin and curcumin analogues on TRP channels. Fitoterapia 122: 126-131. https://doi.org/10.1016/j.fitote.2017.09.007

Navvabi Rigi, S., Kermansaravi, F., Navidian, A., Safabakhsh, L., Safarzadeh, A., Khazaeian, S., Shafie, S. & Salehian, T. 2012. Comparing the analgesic effect of heat patch containing iron chip and ibuprofen for primary dysmenorrhea: A randomized controlled trial. BMC Women’s Health 12: 25. https://doi.org/10.1186/1472-6874-12-25

Nyirenda, T., Nyagumbo, E., Murewanhema, G., Mukonowenzou, N., Kagodora, S.B., Mapfumo, C., Bhebhe, M. & Mufunda, J. 2023. Prevalence of dysmenorrhea and associated risk factors among university students in Zimbabwe. Women’s Health 19: 17455057231189549. https://doi.org/10.1177/17455057231189549

Park, J. 2010. Anti-carcinogenic properties of curcumin on colorectal cancer. World Journal of Gastrointestinal Oncology 2(4): 169. https://doi.org/10.4251/wjgo.v2.i4.169

Peng, Y., Zheng, X., Fan, Z., Zhou, H., Zhu, X., Wang, G. & Liu, Z. 2020. Paeonol alleviates primary dysmenorrhea in mice via activating CB2R in the uterus. Phytomedicine 68: 153151. https://doi.org/10.1016/j.phymed.2019.153151

Pichardo, E., Liborio-Kimura, T., Caballero, M.E., Kandany, V.N., Mena, L., Ferreira-Filho, E., Almeida, E.D., Navia, S.B., Zelniker, M., Matsuura, D., Ying, C.T.Q., Calabria, B.S.R., De Almeida, G., Mushtaq, K., Abdallah, A., Doomi, A., Antonio, E.P. & Tamayo, A. 2020. ESCAPE pain trial - The effects of Curcumin in pain relief in women diagnosed with primary dysmenorrhea: A triple-blinded, placebo-controlled, phase II, randomized clinical trial protocol. Principles and Practice of Clinical Research 6(2): 25-32. https://doi.org/10.21801/ppcrj.2020.62.5

Sharghi, M., Mansurkhani, S.M., Ashtary-Larky, D., Kooti, W., Niksefat, M., Firoozbakht, M., Behzadifar, M., Azami, M., Servatyari, K. & Jouybari, L. 2019. An update and systematic review on the treatment of primary dysmenorrhea. Jornal Brasileiro de Reproducao Assistida 23(1): 51-57. https://doi.org/10.5935/1518-0557.20180083

Sulastri, S., Wiratmini, N.I. & Suriani, N.L. 2014. Panjang siklus estrus mencit (Mus musculus L.) yang diberi pemanis buatan aspartam secara oral. Jurnal Biologi 18(2): 69-72. https://doi.org/jurnal.harianregional.com/bio/id-16839

Tabari, N.S., Kheirkhah, M., Mojab, F. & Salehi, M. 2020. An investigation of the effect of curcumin (turmeric) capsule on the severity and duration of dysmenorrhea in students of Iran University of Medical Sciences. Journal of Evolution of Medical and Dental Sciences 9(46): 3444-3451. https://doi.org/10.14260/jemds/2020/755

Uddin, S.J., Hasan, M.F., Afroz, M., Sarker, D.K., Rouf, R., Islam, M.T., Shilpi, J.A. & Mubarak, M.S. 2021. Curcumin and its multi-target function against pain and inflammation: An update of pre-clinical data. Curr. Drug Targets 22(6): 656-671. https://doi.org/10.2174/1389450121666200925150022

Verma, S., Mundkinajeddu, D., Agarwal, A., Chatterjee, S.S. & Kumar, V. 2017. Effects of turmeric curcuminoids and metformin against central sensitivity to pain in mice. Journal of Traditional and Complementary Medicine 7(2): 145-151. https://doi.org/10.1016/j.jtcme.2016.04.001

Wang, L., Yan, Y., Qiu, H., Xu, D., Zhu, J., Liu, J. & Li, H. 2022. Prevalence and risk factors of primary dysmenorrhea in students: A meta-analysis. Value in Health 25(10): 1678-1684. https://doi.org/10.1016/j.jval.2022.03.023

Wang, S., Joseph, J., Ro, J.Y. & Chung, M-K. 2015. Modality-specific mechanisms of protein kinase C–induced hypersensitivity of TRPV1. Pain 156(5): 931-941. https://doi.org/10.1097/j.pain.0000000000000134

Yang, L., Cao, Z., Yu, B. & Chai, C. 2015. An in vivo mouse model of primary dysmenorrheal. Experimental Animals 64(3): 295-303. https://doi.org/10.1538/expanim.14-0111

Yang, M., Wang, J., Yang, C., Han, H., Rong, W. & Zhang, G. 2017. Oral administration of curcumin attenuates visceral hyperalgesia through inhibiting phosphorylation of TRPV1 in rat model of ulcerative colitis. Molecular Pain 13: 1744806917726416. https://doi.org/10.1177/1744806917726416

Yang, Z., He, C., He, J., Chu, J., Liu, H. & Deng, X. 2018. Curcumin-mediated bone marrow mesenchymal stem cell sheets create a favorable immune microenvironment for adult full-thickness cutaneous wound healing. Stem Cell Research and Therapy 9: 21. https://doi.org/10.1186/s13287-018-0768-6

Yeon, K.Y., Kim, S.A., Kim, Y.H., Lee, M.K., Ahn, D.K., Kim, H.J., Kim, J.S., Jung, S.J. & Oh, S.B. 2009. Curcumin produces an antihyperalgesic effect via antagonism of TRPV1. Journal of Dental Research 89(2): 170-174. https://doi.org/10.1177/0022034509356169

Yu, L., Yi-qin, W., Ling-yu, C., Bin-qian, M., Xiao-xian, W., Yao, X. & Biao, T. 2019. Effect of electroacupuncture on NF-κB and NLRP3 rats with primary dysmenorrhea inflammasome in uterine tissues of rats with primary dysmenorrhea. Journal of Acupuncture and Tuina Science 17(4): 215-222. https://doi.org/10.1007/s11726-019-1117-8

Zhi, L., Dong, L., Kong, D., Sun, B., Sun, Q., Grundy, D., Zhang, G. & Rong, W. 2013. Curcumin acts via transient receptor potential vanilloid-1 receptors to inhibit gut nociception and reverses visceral hyperalgesia. Neurogastroenterology & Motility 25(6): e429-e440. https://doi.org/10.1111/nmo.12145

*Pengarang untuk surat-menyurat; email: khairul_purba@fk.unair.ac.id