DOI QR코드

DOI QR Code

Silymarin attenuates escitalopram (cipralex) induced pancreatic injury in adult male albino rats: a biochemical, histological, and immunohistochemical approach

  • Rasha Mamdouh Salama (Department of Anatomy and Embryology, Faculty of Medicine, Menoufia University) ;
  • Sara Gamal Tayel (Department of Anatomy and Embryology, Faculty of Medicine, Menoufia University)
  • Received : 2022.10.13
  • Accepted : 2022.11.25
  • Published : 2023.03.31

Abstract

Depression is a prevalent global problem since ages, predominately treated with SSRI. Cipralex, is an antidepressant of the SSRIs class used as a remedy for mood, depression and anxiety. Silymarin (SIL), a natural free radical scavenging, has an antioxidant and anti-inflammatory properties. This hypothesis evaluates, for the first time, the role of cipralex on the structure of the endocrine and exocrine components of the pancreas and assess the beneficial effects of SIL on these changes. Forty-five rats were divided into control, cipralex, and cipralex plus SIL groups. During sacrifice, all rats and pancreases were weighed and the ratio of pancreatic weight (PW) to rat weight (RW) was calculated, blood samples were collected to estimate fasting glucose, insulin and amylase levels, the specimens were prepared for histological, immunohistochemical (inducible nitric oxide synthase [iNOS], tumour necrosis factor-alpha [TNF-α], caspase 3, proliferating cell nuclear antigen [PCNA], and anti-insulin antibody), and morphometrical studies. Cipralex group exhibited marked destruction of the pancreatic architecture of the exocrine and endocrine parts, with a dense collagen fiber deposition. Also, there is highly significant decrease (P<0.001) of PW/RT ratio, insulin, and amylase levels, the number and diameter of islets of Langerhans, the number of PCNA positive immunoreactive cells, and the number of insulin positive β-cells. Furthermore, a highly significant increase of glucose level, iNOS, TNF-α, and caspase-3 positive immunoreactive cells in the islets of Langerhans and acinar cells were observed. SIL improves the pancreatic histological architecture, weight loss, biochemical, and immunohistochemical analyses. Administering SIL is advantageous in managing cipralex induced pancreatic injury via its anti-inflammatory, antioxidant, and anti-apoptotic qualities.

Keywords

References

  1. World Health Organization. Depression fact. 2012. Sheet no. 369 [Internet]. Geneva: WHO; 2012 [cited 2022 Oct 3]. Available from: http://www.who.int/mediacentre/factsheets/fs369/en/.
  2. Lochmann D, Richardson T. Selective serotonin reuptake inhibitors. Handb Exp Pharmacol 2019;250:135-44.
  3. Pirraglia PA, Stafford RS, Singer DE. Trends in prescribing of selective serotonin reuptake inhibitors and other newer antidepressant agents in adult primary care. Prim Care Companion J Clin Psychiatry 2003;5:153-7.
  4. Pastoor D, Gobburu J. Clinical pharmacology review of escitalopram for the treatment of depression. Expert Opin Drug Metab Toxicol 2014;10:121-8.
  5. Standring S. Gray's anatomy: the anatomical basis of clinical practice. 41th ed. Philadelphia: Elsevier; 2016. p. 1183-90.
  6. Tiwari AK, Rao JM. Diabetes mellitus and multiple therapeutic approaches of phytochemicals: present status and future prospects. Curr Sci 2002;83:30-8.
  7. Hall JE. Secretory function of the alimentary tract. In: Guyton AC, Hall JE, editors. Textbook of Medical Physiology. 11th ed. Philadelphia: Elsevier Saunders; 2006. p.791-807.
  8. Peng C, Tu G, Yu L, Wu P, Zhang X, Li Z, Li Z, Yu X. Murine chronic pancreatitis model induced by partial ligation of the pancreatic duct encapsulates the profile of macrophage in human chronic pancreatitis. Front Immunol 2022;13:840887.
  9. Lee PJ, Papachristou GI. New insights into acute pancreatitis. Nat Rev Gastroenterol Hepatol 2019;16:479-96.
  10. Petrov MS, Yadav D. Global epidemiology and holistic prevention of pancreatitis. Nat Rev Gastroenterol Hepatol 2019;16:175-84.
  11. Beyer G, Habtezion A, Werner J, Lerch MM, Mayerle J. Chronic pancreatitis. Lancet 2020;396:499-512.
  12. Romeh GH, El-Safty FEA, El-Mehi AE, Faried MA. Antioxidant, anti-inflammatory, and anti-fibrotic properties of olive leaf extract protect against L-arginine induced chronic pancreatitis in the adult male albino rat. Anat Cell Biol 2022;55:205-16.
  13. Lohr JM. What are the useful biological and functional markers of early-stage chronic pancreatitis? J Gastroenterol 2007;42(Suppl 17):66-71.
  14. Kvande KT, Madsen S. [Selective serotonin uptake inhibitors and pancreatitis]. Tidsskr Nor Laegeforen 2001;121:177-8. Norwegian.
  15. Lin H, Liao K, Chang C, Lin C, Lai S. Association of use of selective serotonin reuptake inhibitors with risk of acute pancreatitis: a case-control study in Taiwan. Eur J Clin Pharmacol 2017;73:1615-21.
  16. Ljung R, Ruck C, Mattsson F, Bexelius TS, Lagergren J, Lindblad M. Selective serotonin reuptake inhibitors and the risk of acute pancreatitis: a Swedish population-based case-control study. J Clin Psychopharmacol 2012;32:336-40.
  17. Khoza S, Barner JC, Bohman TM, Rascati K, Lawson K, Wilson JP. Use of antidepressant agents and the risk of type 2 diabetes. Eur J Clin Pharmacol 2012;68:1295-302.
  18. Pan A, Sun Q, Okereke OI, Rexrode KM, Rubin RR, Lucas M, Willett WC, Manson JE, Hu FB. Use of antidepressant medication and risk of type 2 diabetes: results from three cohorts of US adults. Diabetologia 2012;55:63-72.
  19. Wu C, Gau SS, Lai M. Long-term antidepressant use and the risk of type 2 diabetes mellitus: a population-based, nested case-control study in Taiwan. J Clin Psychiatry 2014;75:31-8; quiz 38.
  20. Monobe M, Ogino A, Ema K, Tokuda Y, Maeda-Yamamoto M. A crude extract from immature green tea (Camellia sinensis) leaves promotes Toll-like receptor 7-mediated interferon-α production in human macrophage-like cells. Cytotechnology 2012;64:145-8.
  21. Tabassum N, Hamdani M. Plants used to treat skin diseases. Pharmacogn Rev 2014;8:52-60.
  22. Abenavoli L, Capasso R, Milic N, Capasso F. Milk thistle in liver diseases: past, present, future. Phytother Res 2010;24:1423-32.
  23. Federico A, Dallio M, Loguercio C. Silymarin/silybin and chronic liver disease: a marriage of many years. Molecules 2017;22:191.
  24. Bahmani M, Shirzad H, Rafieian S, Rafieian-Kopaei M. Silybum marianum: beyond Hepatoprotection. J Evid Based Complementary Altern Med 2015;20:292-301.
  25. Vargas-Mendoza N, Madrigal-Santillan E, Morales-Gonzalez A, Esquivel-Soto J, Esquivel-Chirino C, Garcia-Luna Y Gonzalez-Rubio M, Gayosso-de-Lucio JA, Morales-Gonzalez JA. Hepatoprotective effect of silymarin. World J Hepatol 2014;6:144-9.
  26. Ying X, Sun L, Chen X, Xu H, Guo X, Chen H, Hong J, Cheng S, Peng L. Silibinin promotes osteoblast differentiation of human bone marrow stromal cells via bone morphogenetic protein signaling. Eur J Pharmacol 2013;721:225-30.
  27. Soto C, Raya L, Juarez J, Perez J, Gonzalez I. Effect of Silymarin in Pdx-1 expression and the proliferation of pancreatic β-cells in a pancreatectomy model. Phytomedicine 2014;21:233-9.
  28. Ramakrishnan G, Lo Muzio L, Elinos-Baez CM, Jagan S, Augustine TA, Kamaraj S, Anandakumar P, Devaki T. Silymarin inhibited proliferation and induced apoptosis in hepatic cancer cells. Cell Prolif 2009;42:229-40.
  29. Wu C, Gong WG, Wang YJ, Sun JJ, Zhou H, Zhang ZJ, Ren QG. Escitalopram alleviates stress-induced Alzheimer's disease-like tau pathologies and cognitive deficits by reducing hypothalamic-pituitary-adrenal axis reactivity and insulin/GSK-3β signal pathway activity. Neurobiol Aging 2018;67:137-47.
  30. Kabel AM, Mahmoud HA, El Kholy SS. Ameliorative potential of gemfibrozil and silymarin on experimentally induced nephrotoxicity in rats. Afr J Urol 2013;19:171-8.
  31. Kim M, Kim D, Choi J, Kim D, Song H, Bae G, Park S. Silymarin attenuates the severity of cerulein-induced acute pancreatitis. Pancreas 2020;49:89-95.
  32. Trinder P. Determination of blood glucose using an oxidase-peroxidase system with a non-carcinogenic chromogen. J Clin Pathol 1969;22:158-61.
  33. Landt M, Hortin GL, Smith CH, Pashos G, Vaidya HC, Rosenblum JL. Rapid measurement of serum pancreatic amylase. J Clin Lab Anal 1994;8:10-5.
  34. Suvarna SK, Layton C, Bancroft JD. Bancroft's theory and practice of histological techniques. 8th ed. London: Elsevier; 2019. p. 126-38.
  35. Suvarna SK, Layton C, Bancroft JD. Bancroft's theory and practice of histological techniques. 8th ed. London: Elsevier; 2019. p. 337-94.
  36. Soliman NB. Effect of chronic immobilization stress on the pancreatic structure and the possible protective role of testosterone administration in male albino rats. Egypt J Histol 2012;35:448-57.
  37. Hidayati DYN, Sujuti H, Wulandari L, Saputra AD, Santoso GA. TNF-α (Tumor Necrosis Factor Alpha) and iNOS (Inducible Nitric Oxide Synthase) expression in rat brain infected by mycobacterium tuberculosis strain H37RV. J Tuberc Res 2017;5:58-68.
  38. Witt H, Apte MV, Keim V, Wilson JS. Chronic pancreatitis: challenges and advances in pathogenesis, genetics, diagnosis, and therapy. Gastroenterology 2007;132:1557-73.
  39. Kim JW, Ko SH, Cho JH, Sun C, Hong OK, Lee SH, Kim JH, Lee KW, Kwon HS, Lee JM, Song KH, Son HY, Yoon KH. Loss of beta-cells with fibrotic islet destruction in type 2 diabetes mellitus. Front Biosci 2008;13:6022-33.
  40. Ismail OZ, Bhayana V. Lipase or amylase for the diagnosis of acute pancreatitis? Clin Biochem 2017;50:1275-80.
  41. Sano T, Ozaki K, Matsuura T, Narama I. Giant mitochondria in pancreatic acinar cells of alloxan-induced diabetic rats. Toxicol Pathol 2010;38:658-65.
  42. Akpan OU, Bassey RB, Agba BS, Edegha IA. Elevation of serum pancreatic amylase and distortion of pancreatic cytoarchitecture in type 1 diabetes mellitus rats treated with Ocimum gratissimum. Niger Med J 2014;55:34-8.
  43. Yang J, Tang X, Wu Q, Ren P, Yan Y. A severe acute pancreatitis mouse model transited from mild symptoms induced by a "Two-Hit" strategy with L-arginine. Life (Basel) 2022;12:126.
  44. Ma J, Meng X, Liu Y, Yin C, Zhang T, Wang P, Park YK, Jung HW. Effects of a rhizome aqueous extract of Dioscorea batatas and its bioactive compound, allantoin in high fat diet and streptozotocin-induced diabetic mice and the regulation of liver, pancreas and skeletal muscle dysfunction. J Ethnopharmacol 2020;259:112926.
  45. Chan K, Truong D, Shangari N, O'Brien PJ. Drug-induced mitochondrial toxicity. Expert Opin Drug Metab Toxicol 2005;1:655-69.
  46. Curti C, Mingatto FE, Polizello AC, Galastri LO, Uyemura SA, Santos AC. Fluoxetine interacts with the lipid bilayer of the inner membrane in isolated rat brain mitochondria, inhibiting electron transport and F1F0-ATPase activity. Mol Cell Biochem 1999;199:103-9.
  47. Abdel-Razaq W, Kendall DA, Bates TE. The effects of antidepressants on mitochondrial function in a model cell system and isolated mitochondria. Neurochem Res 2011;36:327-38.
  48. Li Y, Couch L, Higuchi M, Fang JL, Guo L. Mitochondrial dysfunction induced by sertraline, an antidepressant agent. Toxicol Sci 2012;127:582-91.
  49. Elmorsy E, Al-Ghafari A, Helaly ANM, Hisab AS, Oehrle B, Smith PA. Editor's highlight: therapeutic concentrations of antidepressants inhibit pancreatic beta-cell function via mitochondrial complex inhibition. Toxicol Sci 2017;158:286-301.
  50. Zerem E. Treatment of severe acute pancreatitis and its complications. World J Gastroenterol 2014;20:13879-92.
  51. Kaukonen KM, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med 2015;372:1629-38.
  52. Suarez EC. C-reactive protein is associated with psychological risk factors of cardiovascular disease in apparently healthy adults. Psychosom Med 2004;66:684-91.
  53. Yao S, Li J, Fan X, Liu Q, Lian J. The effect of selective serotonin re-uptake inhibitors on risk of type II diabetes mellitus and acute pancreatitis: a meta-analysis. Biosci Rep 2018;38:BSR20180967.
  54. Isaac R, Boura-Halfon S, Gurevitch D, Shainskaya A, Levkovitz Y, Zick Y. Selective serotonin reuptake inhibitors (SSRIs) inhibit insulin secretion and action in pancreatic β cells. J Biol Chem 2013;288:5682-93. Erratum in: J Biol Chem 2018;293:4577-8.
  55. Paulmann N, Grohmann M, Voigt JP, Bert B, Vowinckel J, Bader M, Skelin M, Jevsek M, Fink H, Rupnik M, Walther DJ. Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation. PLoS Biol 2009;7:e1000229.
  56. Arisha SM. Alpha-lipoic acid-role in improving both reserpine toxicity and paroxetine treatment in the cerebral cortex of albino rats; histological, ultrastructural, immunohistohemical and biochemical studies. Beni-Suef Univ J Basic Appl Sci 2022;11:86.
  57. Surai PF. Silymarin as a natural antioxidant: an overview of the current evidence and perspectives. Antioxidants (Basel) 2015;4:204-47.
  58. Bijak M. Silybin, a major bioactive component of milk thistle (Silybum marianum L. Gaernt.)-chemistry, bioavailability, and metabolism. Molecules 2017;22:1942.
  59. Triantafillidis JK, Triantafyllidi E, Sideris M, Pittaras T, Papalois AE. Herbals and plants in the treatment of pancreatic cancer: a systematic review of experimental and clinical studies. Nutrients 2022;14:619.
  60. Amniattalab A, Malekinejad H, Rezabakhsh A, Rokhsartalab-Azar S, Alizade-Fanalou S. Silymarin: a novel natural agent to restore defective pancreatic β cells in streptozotocin (STZ)-induced diabetic rats. Iran J Pharm Res 2016;15:493-500.
  61. Khakinezhad Tehrani F, Ranji N, Kouhkan F, Hosseinzadeh S. Apoptosis induction and proliferation inhibition by silibinin encapsulated in nanoparticles in MIA PaCa-2 cancer cells and deregulation of some miRNAs. Iran J Basic Med Sci 2020;23:469-82.