Emre ARSLANBAŞ, Haki KARA, Nergiz Hacer TURGUT, Hüseyin GÜNGÖR, Halef Okan DOĞAN, Mustafa Ozan ATASOY, Alper Serhat KUMRU

The Effect of Greater Celandine Active Ingredient Chelidonine on Isolated Rat Bladder and Trachea Smooth Muscles and Primary Lung and Kidney Cell Lines

This study aims to explore the pharmacodynamics of chelidonine, the active ingredient in greater celandine (Chelidonium majus L.), on in vitro rat bladder and trachea tissue, and evaluate its cell protective effects on primary lung and kidney cell lines. The study was carried out via repeated applications of acetylcholine, atropine, verapamil and oxybutynin, alongside Ca++ in a calcium-free environment, on urinary bladder tissue, and repeated applications of acetylcholine, atropine, carbachol and mecamylamine on trachea tissue. At the same time, cell viability and catalase and superoxide dismutase activity was measured on primary cell lines obtained from lung and kidney tissue samples. The study has shown that chelidonine has a relaxant effect on bladder and trachea tissues, and it may be mentioned that this effect is produced via muscarinic receptors. In addition, chelidonin caused a statistically insignificant increase in cell viability in primary lung and kidney cell lines at increasing doses (1 and 4 μg/ mL), but this increase remained at the control group level. In contrast, chelidonin caused a significant decrease in cell viability at the same cell lines at doses of 8 and 16 μg/mL. In conclusion, it is suggested that greater celandine, which is used in folk medicine, and its active ingredient chelidonine might have beneficial effects on asthma, urinary incontinence and other urinary tract and respiratory diseases among others.

Kırlangıç Otu Etkin Maddesi Chelidoninin İzole Rat İdrar Kesesi ve Trakea Düz Kasları ve Primer Akciğer ve Böbrek Hücre Hatları Üzerine Etkisi

Bu çalışmada, kırlangıç otu (Chelidonium majus L.) etkin maddesi chelidoninin in vitro rat idrar kesesi ve trakea dokusu üzerindeki farmakodinamik etkilerinin değerlendirilmesi ve primer akciğer ve böbrek hücre hatları üzerine hücre koruyucu etkilerinin araştırılması amaçlandı. Çalışma, idrar kesesi dokusunda tekrarlı yapılan asetilkolin, atropin, verapamil ve oksibutinin ile kalsiyumsuz ortamda Ca++ uygulamalarıyla, trakea dokusuna ise tekrarlı uygulamalarla asetilkolin, atropin, karbakol ve mekamilamin verilerek gerçekleştirildi. Aynı zamanda, alınan akciğer ve böbrek dokularından elde edilen primer hücre hatları üzerinde hücre canlılığı ölçümleri, katalaz ve süperoksit dismutaz enzim aktivitelerinin tayini yapıldı. Çalışma sonucunda, kırlangıç otu etkin maddesi chelidoninin idrar kesesi ve trakea dokuları üzerinde gevşetici etkisinin olduğu belirlendi ve chelidoninin bu etkisini muskarinik reseptörler üzerinden gösterdiğinden söz edilebilir. Ayrıca, chelidonin artan dozlarda (1 ve 4 μg/mL) primer akciğer ve böbrek hücre hatlarında hücre canlılığında istatistiksel olarak önemsiz bir artışa neden oldu, ancak bu artış kontrol grubu seviyesinde kaldı. Buna karşılık chelidonin aynı hücre hatlarında 8 ve 16 μg/mL dozlarında hücre canlılığında önemli bir düşüşe neden oldu. Sonuç olarak, halk arasında tıbbi amaçlarla kullanılan kırlangıç otunun ve etkin maddesi chelidonin astım, üriner inkontinans, idrar yolları ve solunum sistemi hastalıkları vb. durumlarda faydalı etkileri olabileceği görüşüne varıldı.

PDF

___

1. Koriem KMM, Arbid MS, Asaad GF: Chelidonium majus leaves methanol extract and its chelidonine alkaloid ingredient reduce cadmium-induced nephrotoxicity in rats. J Nat Med, 67, 159-167, 2013. DOI: 10.1007/s11418-012- 0667-6

2. Orvos P, Virág L, Tálosi L, Hajdú Z, Csupor D, Jedlinszki N, Szél T, Varró A, Hohmann J: Effects of Chelidonium majus extracts and major alkaloids on hERG potassium channels and on dog cardiac action potential-A safety approach. Fitoterapia, 100, 156-165, 2015. DOI: 10.1016/ j.fitote.2014.11.023

3. Jesionek W, Fornal E, Majer-Dziedzic B, Móricz ÁM, Nowicky W, Choma IM: Investigation of the composition and antibacterial activity of UkrainTM drug using liquid chromatography techniques. J Chromatogr A, 1429, 340-347, 2016. DOI: 10.1016/j.chroma.2015.12.015

4. Erdil Z: Chelidonium majus L. türü ve alkaloitlerinin farmakolojik etkileri. Eczacı Odası Yayınları-Ölçek, 2: 18-23, 1992.

5. Capistrano IR, Wouters A, Lardon F, Gravekamp C, Apers S, Pieters L: In vitro and in vivo investigations on the antitumour activity of Chelidonium majus. Phytomedicine, 22, 1279-1287, 2015. DOI: 10.1016/j.phymed.2015.10.013

6. Philchenkov A, Kaminskyy V, Zavelevich M, Stoika R: Apoptogenic activity of two benzophenanthridine alkaloids from Chelidonium majus L. does not correlate with their DNA damaging effects. Toxicol In Vitro, 22, 287-295, 2008. DOI: 10.1016/j.tiv.2007.08.023

7. Kökçü B, Esen O, Uysal İ: Medicinal plants sold in Çanakkale/Turkey city center herbalists. BioDiCon, 8 (3): 80-91, 2015.

8. Kim SH, Hong J, Lee YC: Chelidonine, a principal isoquinoline alkaloid of Chelidonium majus, attenuates eosinophilic airway inflammation by suppressing IL-4 and eotaxin-2 expression in asthmatic mice. Pharmacol Rep, 67, 1168-1177, 2015. DOI: 10.1016/j.pharep.2015.04.013

9. Havelek R, Seifrtova M, Kralovec K, Krocova E, Tejkalova V, Novotny I, Cahlikova L, Safratova M, Opletal L, Bilkova Z, Vavrova J, Rezacova M: Comparative cytotoxicity of chelidonine and homochelidonine, the dimethoxy analogues isolated from Chelidonium majus L. (Papaveraceae), against human leukemic and lung carcinoma cells. Phytomedicine, 23, 253-266, 2016. DOI: 10.1016/j.phymed.2016.01.001

10. Boegge SC, Kesper S, Verspohl EJ, Nahrstedt A: Reduction of AChinduced contraction of rat isolated ileum by coptisine, (+)-caffeoylmalic acid, Chelidonium majus, and Corydalis lutea extracts. Planta Med, 62 (2): 173-174, 1996. DOI: 10.1055/s-2006-957845

11. Hiller K, Ghorbani M, Schilcher H: Antispasmodic and relaxant activity of chelidonine, protopine, coptisine, and Chelidonium majus extracts on isolated guinea-pig ileum. Planta Med, 64 (8): 758-760, 1998. DOI: 10.1055/s-2006- 957576

12. Heinle H, Hagelauer D, Pascht U, Kelber O, Weiser D: Intestinal spasmolytic effects of STW 5 (Iberogasts) and its components. Phytomedicine, 13, 75-79, 2006. DOI: 10.1016/j.phymed.2006.03.013

13. Kuenzel J, Geisler K, Strahl O, Grundtner P, Beckmann MW, Dittrich R: Chelidonium majus and its effects on uterine contractility in a perfusion model. Eur J Obstet Gynecol Reprod Biol, 169, 213-217, 2013. DOI: 10.1016/j. ejogrb.2013.03.014

14. Kaminskyy V, Kulachkovskyy O, Stoika R: A decisive role of mitochondria in defining rate and intensity of apoptosis induction by different alkaloids. Toxicol Lett, 177, 168-181, 2008. DOI: 10.1016/j.toxlet.2008.01.009

15. Noureini SK, Esmaili H: Multiple mechanisms of cell death induced by chelidonine in MCF-7 breast cancer cell line. Chem Biol Interact, 223, 141- 149, 2014. DOI: 10.1016/j.cbi.2014.09.013

16. Çelebi F, Doğan A: Bazı yerel anestezik ilaçların (lidokain, bupivakain, prilokain) ratlarda mesane kasları üzerine in vitro etkisi. Kafkas Univ Vet Fak Derg, 6 (1-2): 47-53, 2000.

17. Baydan E, Kartal M, Yurdakök B, Erdem SA, İnce S, Ekici H, Alp H: Contractile effects of Eryngium kotschyi Boiss. on rat isolated ileum and detrussor muscle. Kafkas Univ Vet Fak Derg, 20 (5): 779-785, 2014. DOI: 10.9775/ kvfd.2014.11110

18. Estrada-Soto S, Sánchez-Recillas A, Navarrete-Vázquez G, Castillo- Espaňa P, Villalobos-Molina R, Ibarra-Barajas M: Relaxant effects of Artemisia ludoviciana on isolated rat smooth muscle tissues. J Ethnopharmacol, 139, 513-518, 2012. DOI: 10.1016/j.jep.2011.11.041

19. Yıldırım E: Tavşan trakeası üzerine levamizolun etkisinin tek başına ve triklorfonla birlikte araştırılması. Ankara Üniv Vet Fak Derg, 52: 23-28, 2005.

20. Vasconcelos TB, Ribeiro-Filho HV, Lucetti LT, Magalhães PJC: β-Citronellol, an alcoholic monoterpene with inhibitory properties on the contractility of rat trachea. Braz J Med Biol Res, 49 (2): 1-9, 2016. DOI: 10.1590/ 1414-431X20154800

21. Freshney RI: Primary culture. In, Freshney RI (Ed): Culture of Animal Cells: A Manual of Basic Technique and Specialized Applications. 6th ed., 163-187, John Wiley&Sons, Inc., New Jersey, 2010.

22. Akan H, Bakır Sade Y: Kâhta (Adıyaman) merkezi ve Narince Köyü’nün etnobotanik açıdan araştırılması. BEÜ Fen Bilimleri Derg, 4 (2): 219-248, 2015.

23. Uchiyama T, Chess-Williams R: Muscarinic receptor subtypes of the bladder and gastrointestinal tract. J Smooth Muscle Res, 40, 237-247, 2004. DOI: 10.1540/jsmr.40.237

24. Abraham G: The importance of muscarinic receptors in domestic animal diseases and therapy: Current and future perspectives. Vet J, 208, 13-21, 2016. DOI: 10.1016/j.tvjl.2015.10.025

25. Yarker YE, Goa KL, Fitton A: Oxybutynin: A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic use in detrusor instability. Drugs Aging, 6, 243-262, 1995. DOI: 10.2165/ 00002512-199506030-00007

26. Xing H, Luo X, Li Y, Fan C, Liu N, Cui C, Li W: Effect of verapamil on the pharmacokinetics of hydroxycamptothecin and its potential mechanism. Pharm Biol, 58, 152-156, 2020. DOI: 10.1080/13880209.2020.1717550

27. Metzen J, Bittinger F, Kirkpatrick CJ, Kilbinger H, Wessler I: Proliferative effect of acetylcholine on rat trachea epithelial cells is mediated by nicotinic receptors and muscarinic receptors of the M1-subtype. Life Sci, 72, 2075‐2080, 2003. DOI: 10.1016/s0024-3205(03)00086-9

28. Kadota H, Kuwahara M, Nishibata R, Mikami H, Tsubone H: Effect of M2 and M3 muscarinic receptors on airway responsiveness to carbachol in bronchial-hypersensitive (BHS) and bronchial-hyposensitive (BHR) guinea pigs. Exp Anim, 50, 49‐58, 2001. DOI: 10.1538/expanim.50.49

29. Purnyn’ EÉ, Voitenko SV, Remizov IN, Rikhal’sky OV, Skok VI: Mechanism underlying the effect of mecamylamine on nicotinic acetyl-choline receptors of rat sympathetic ganglion neurons. Neurophysiology, 33, 28-32, 2001.

30. Hammerová J, Uldrijan S, Táborská E, Slaninová I: Benzo[c] phenanthridine alkaloids exhibit strong anti-proliferative activity in malignant melanoma cells regardless of their p53 status. J Dermatol Sci, 62, 22-35, 2011. DOI: 10.1016/j.jdermsci.2011.01.006

31. Paul A, Das J, Das S, Samadder A, Khuda-Bukhsh AR: Poly (lactideco- glycolide) nano-encapsulation of chelidonine, an active bioingredient of greater celandine (Chelidonium majus), enhances its ameliorative potential against cadmium induced oxidative stress and hepatic injury in mice. Environ Toxicol Pharmacol, 36, 937-947, 2013. DOI: 10.1016/j.etap.2013.08.008

32. Kaminskyy V, Lin KW, Filyak Y, Stoika R: Differential effect of sanguinarine, chelerythrine and chelidonine on DNA damage and cell viability in primary mouse spleen cells and mouse leukemic cells. Cell Biol Int, 32, 271-277, 2008. DOI: 10.1016/j.cellbi.2007.09.004