Document Type : Original Research Article

Authors

1 Department of Pharmacy, Faculty of Health Science, University of Muhammadiyah Malang, Malang, Indonesia

2 Department of Pharmacy, Faculty of Medicine and Health Science, Maulana Malik Ibrahim State Islamic University, Malang, Indonesia

Abstract

Pain and inflammation in the joints from cartilage breakdown characterize osteoarthritis (OA), a degenerative disease linked to low estrogen levels. Because phytoestrogens can perform the same role as estrogen, they may be useful in relieving OA-related pain and inflammation. It is well-documented that some plants, like Chrysophyllum cainito L., contain phytoestrogens. To identify the efficacy of a 70% ethanol extract (CLE) and tablet (CLT) formulated from C. cainito leaves in reducing pain perception in male Wistar rats. Acute toxicity tests were initially carried out on the CLE in rats. The analysis was carried out for 14 days, and then a probit analysis was performed to determine the LD50 value. The antinociceptive activity of CLE and CLT was then tested on rats using the writhing test at doses of 4.05, 8.1, and 16.2 mg/200 g BW rat/day for the CLE, and 24.3, 48.6, and 97.2 mg/200 g BW rat/day for the CLT. After 30 minutes of administration of each sample, the rats were induced intraperitoneally with 1% acetic acid and then observed for their stretch for 30 minutes. The LD50 for the CLE was 70.028 g/kg, indicating that it was practically non-toxic. The rats also showed no signs of toxicity qualitatively. Both the CLE and CLT demonstrated antinociceptive activity, with the optimal dose for CLE being 4.05 mg/200 g BW, and the optimal dose for CLT being 48.6 mg/200 g BW, resulting in percentages of writhing inhibition of 80.61 ± 7.3 and 80.62 ± 7.3, respectively. These results indicate that CLE and CLT are safe and have an antinociceptive effect, so they have the potential to be developed as alternative anti-OA drugs.

Graphical Abstract

The antinociceptive effect of Chrysophyllum cainito L. leaves extract and tablet in wistar rats

Keywords

[1] K.L. Barker, F. Toye, K. Seers, A synthesis of qualitative research to understand the complexity behind treatment decision-making for osteoarthritis, Osteoarthr Cartil Open, 2023, 5, 100355. [Crossref], [Google Scholar], [Publisher]  
[2] Y. Zhang, J. Yang, T. Yu, L. Ma, Y. Cheng, X. Li, Epidemiological Characteristics of Osteoarthritis in Yichang City-Hubei Province, China, 2017–2018, China CDC Wkly, 2021, 3, 335. [Crossref], [Google Scholar], [Publisher]  
[3] Ministry of Health of the Republic of Indonesia, RISKESDAS National Report 2018 Health Research and Development Agency, 2018. [Crossref], [Google Scholar], [Publisher]  
[4] Y. Mei, J.S. Williams, E.K. Webb, A.K. Shea, M.J. MacDonald, B.K. Al-Khazraji, Roles of Hormone Replacement Therapy and Menopause on Osteoarthritis and Cardiovascular Disease Outcomes: A Narrative Review, Front Rehabil Sci., 2022, 3, 1. [Crossref], [Google Scholar], [Publisher]  
[5] H. Liu, S.M. Zheng, H.F. Xiong, M.S. Alwahibi, X. Niu, Biosynthesis of copperoxide nanoparticles using Abies spectabilis plant extract and analyzing its antinociceptive and anti-inflammatory potency in various mice models, Arab. J. Chem., 2020, 13, 6995. [Crossref], [Google Scholar], [Publisher]  
[6] A. Mobasheri, Future cell and gene therapy for osteoarthritis (OA): Potential for using mammalian protein production platforms, irradiated and transfected protein packaging cell lines for over-production of therapeutic proteins and growth factors, Adv Exp Med Biol., 2020, 1247, 17. [Crossref], [Google Scholar], [Publisher]  
[7] S.S. Fandinata, A. Purnamayanti, P.R. Utami, The effectiveness and safety of diclofenac sodium and piroxicam therapy in osteoarthritis patients at the Surabaya city health center, J. Ilm. Manuntung., 2020, 6, 306. [Crossref], [Google Scholar], [Publisher]  
[8] A. Bunardi, S. Rizkifani, N. Nurmainah, Study of Self-medication Knowledge Level and Behavior on the Use of Analgesic Drugs in Health Students, J Mhs Farm Fak Kedokt UNTAN, 2021, 4, 109. [Crossref], [Google Scholar], [Publisher]  
[9] H.V Doan, T.P. Le, Chrysophyllum cainito: A Tropical Fruit with Multiple Health Benefits, Evidence-based Complement Altern Med., 2020, 2020. [Crossref], [Google Scholar], [Publisher]  
[10] N.I. Utaminingtyas, B. Ma’arif, D.S. Megawati, R.R.D. Atmaja, Activity of 70% Ethanol Extract of Chrysophyllum cainito in Increasing Vertebrae Trabecular Bone Density in Female Mice, Maj Obat Tradis., 2018, 23, 119. [Crossref], [Google Scholar], [Publisher]  
[11] I.Y. Ningsih, S. Zulaikhah, M.A. Hidayat, B. Kuswandi, Antioxidant Activity of Various Kenitu (Chrysophyllum Cainito L.) Leaves Extracts from Jember, Indonesia, Agric Agric Sci Procedia., 2016, 9, 378. [Crossref], [Google Scholar], [Publisher]  
[12] B. Ma’arif, A. Aditama, R. Muti’ah, W.S. Bagawan, R. Amiruddin, R. Rukiana, Profil Metabolit Berbagai Ekstrak Daun Chrysophyllum cainito L. Menggunakan UPLC-QTOF-MS/MS, J Tumbuh Obat Indones., 2019, 12, 10. [Crossref], [Google Scholar], [Publisher]  
[13] P. Riwanti, M.S. Arifin, F.A. Muslikh, D. Amalia, I. Abada, A.P. Aditama, B. Ma’arif, Effect of chrysophyllum cainito l. Leaves on bone formation in vivo and in silico, Trop J Nat Prod Res., 2021, 5, 260. [Crossref], [Google Scholar], [Publisher]  
[14] A. Makiyah, S. Tresnayanti, Acute toxicity test as measured by determination of LD50 of ethanol extract of Iles-iles tuber (Amorphophallus variabilis Bl.) in Wistar Strain White Mice, Maj Kedokt Bandung, 2017, 49, 145-155. [Crossref], [Google Scholar], [Publisher]  
[15] OECD. Test Guideline 425: Acute Oral Toxicity- Up-and-Down Procedure. Guidel Test Chem. 2022, 26. [Crossref], [Google Scholar], [Publisher]
[16] S.W. Adi, W.A. Dwi, I. Fitriana, S.P. Wikan, testing of acute toxicity of herbal Medicines in mice based on the organization for economic co-operation and development (OECD), J Sain Vet., 2015, 33, 234-239. [Crossref], [Google Scholar], [Publisher]   
[17] Food and drug supervisory agency of the Republic of Indonesia, Regulation of the drug and food control agency number 10 of 2022 concerning guidelines for In Vivo preclinical toxicity testing, The food and drug supervisory agency of the Republic of Indonesia, 2022. [Crossref], [Google Scholar], [Publisher]   
[18] W.H.A. Bakarbessy, A.C. Wullur, W.A. Lolo, Analgesic Effect Test of Ethanol Extract of Breadfruit Leaves (Artocarpus altilis) on Wistar Strain White Mice (Rattus Norvegicus), Pharmacon J Ilm Farm., 2016, 5, 220. [Crossref], [Google Scholar], [Publisher]  
[19] Q. Bajuber, D.N. Indiastuti, E. Kusuma, Analgesic Effect of Zingiber cassumunar Roxb Ethanol Extract. in Mice with the Writing Test Method, J. Med. Vet., 2020, 3, 45-50. [Crossref], [Google Scholar], [Publisher]
[20] E.S. Syamsul, F. Andani, S. Budianti, Analgesic activity study of ethanolic extract of callicarpa longifolia Lamk, In Mice. Tradit. Med. J., 2016, 21, 99–103. [Crossref], [Google Scholar], [Publisher]  
[21] F.F. Rahmadanita, M. Agil, N. Purwitasari, Analgesic activity of marsilea crenata leaf N-hexane extract presl. with the wriggling method in mice, J. Islam Pharm., 2022, 6, 68–72. [Crossref], [Google Scholar], [Publisher]
[22] S.P. Jan, The role of nonsteroidal anti-inflammatory drugs (NSAIDs) and non-NSAID analgesics in pain management, Medicinus, 2022, 35, 51–54. [Crossref], [Google Scholar], [Publisher]
[23] B. Ma’arif, H. Fitri, N.L. Saidah, L.A. Najib, A.H. Yuwafi, R.R.D. Atmaja, F.R. Inayatillah, M. R. Dianti, H. Laswati, M. Agil, Prediction of compounds with antiosteoporosis activity in Chrysophyllum cainito L. leaves through in silico approach, J. Basic Clin. Physiol. Pharmacol., 2021, 32, 803-808. [Crossref], [Google Scholar], [Publisher]  
[24] A. Au, A. Feher, L. McPhee, A. Jessa, S. Oh, G. Einstein, Estrogens, inflammation and cognition, Front Neuroendocrinol., 2016, 40, 87. [Crossref], [Google Scholar], [Publisher]  
[25] E.B. Engler-Chiurazzi, C.M. Brown, J.M. Povroznik, J.W. Simpkins, Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury, Prog Neurobiol., 2017, 157, 188. [Crossref], [Google Scholar], [Publisher]