Anti-Inflammatory Effect of Acetylcysteine and Royal Jelly against Fluoxetine-Induced Hepatotoxicity in Rats

Document Type : Original Article

Authors

1 Ministry of Health, Thi Qar Health Directorate, Al Hussain Teaching Hospital, Thi Qar, Iraq

2 Department of Pharmacology and Toxicology, College of Pharmacy, University of Basrah, Basrah, Iraq

Abstract

Background: Hepatic toxicity of antipsychotic drugs needs to be protected by hepatoprotective medications. This study evaluated the antiinflammatory effect of N-acetylcysteine (NAC) and Royal jelly against hepatotoxicity of fluoxetine in rats.
Methods: Thirty adult female rats were divided into five equal groups of 6 rats. Group A was considered negative control. Group B were rats administered orally by fluoxetine (10 mg\kg) to induce hepatotoxicity. Group C were animals pre-treated with oral NAC (200 mg\kg) and then fluoxetine (10 mg\kg). Group D was pre-treated with Royal jelly (150 mg\kg) following the use of fluoxetine (10 mg\kg). Group E was pretreated with oral Royal jelly and NAC following fluoxetine utilization. After completion of 28 days of treatment, the rats were euthanized and a blood sample was collected and evaluated for inflammatory cytokines of tumor necrotizing factor alpha (TNF-α), interleukin-10 (IL10) and oxidative stress biomarkers of malondialdehyde (MDA) and glutathione (GSH) by ELISA.
Results: Fluoxetine induced hepatotoxicity and an increase in inflammatory cytokines such as TNF-α. Royal jelly and NAC showed significant anti-inflammatory and antioxidant effects by reduction in inflammatory cytokines and oxidative parameters.
Conclusion: Both NAC and Royall jelly were shown to have antioxidant and anti-inflammatory activities, even NAC impact was more than Royal jelly against hepato toxicity induced by fluoxetine. 

Keywords


  1. Wernicke JF. Safety and side effect profile of fluoxetine. Expert Opinion on Drug Safety. Taylor Francis. 2004;495-504. DOI: 10.1517/14740338.3.5.495.
  2. Tripathi A, Avasthi A, Desousa A, et al. Prescription pattern of antidepressants in five tertiary care psychiatric centres of India. Indian J Med Res. 2016;143:507-13. DOI: 10.4103/0971-5916.184289. PMID: 27377509.
  3. Lee-Kelland R, Zehra S, Mappa P. Fluoxetine overdose in a teenager resulting in serotonin syndrome, seizure and delayed onset rhabdomyolysis. BMJ Case Rep. 2018;2018:bcr2018225529. DOI:10.1136/bcr-2018-225529.
  4. Mandrioli R, Forti G, Raggi M. Fluoxetine Metabolism and Pharmacological Interactions: The Role of Cytochrome P450. Curr Drug Metab. 2006;7:127-133. DOI: 10.2174/138920006775541561. PMID: 16472103.
  5. Mohamed Kamel GA. Vinpocetine attenuates fluoxetine-induced liver damage in rats; Role of Nrf2 and PPAR-γ. Hum Exp Toxicol. 2021;40:S509-S518. DOI: 10.1177/09603271211051597. PMID: 34669537.
  6. Elgebaly HA, Mosa NM, Allach M, et al. Olive oil and leaf extract prevent fluoxetine-induced hepatotoxicity by attenuating oxidative stress, inflammation and apoptosis. Biomed Pharmacother. 2018;98:446-453. DOI: 10.1016/j.biopha.2017.12.101.
  7. Zlatković J, Todorović N, Tomanović N, et al. Chronic administration of fluoxetine or clozapine induces oxidative stress in rat liver: A histopathological study. Eur J Pharm Sci. 2014;59:20-30. DOI: 10.1016/j.ejps.2014.04.010. PMID: 24768740.
  8. Tardiolo G, Bramanti P, Mazzon E. Overview on the effects of N-acetylcysteine in neurodegenerative diseases. Molecules. 2018;23: 3305. DOI: 10.3390/molecules23123305. PMID: 30551603.
  9. Aldini G, Altomare A, Baron G, et al. N-Acetylcysteine as an antioxidant and disulphide breaking agent: the reasons why. Free Radic Res. 2018;751-762. DOI: 10.1080/10715762.2018.1468564.
  10. Greiner R, Pálinkás Z, Bäsell K, et al. Polysulfides link H2S to protein thiol oxidation. Antioxidants Redox Signaling. 2013;19:1749-1765. DOI: 10.1089/ars.2012.5041.
  11. Gu L, Zeng H, Maeda K. 10-Hydroxy-2-Decenoic Acid in Royal Jelly Extract Induced Both Filaggrin and Amino Acid in a Cultured Human Three-Dimensional Epidermis Model. Cosmetics. 2017;4:48. DOI: 10.3390/cosmetics4040048.
  12. Hosseini SV, Niknahad H, Fakhar N, et al The Healing Effect Of Honey, Putty, Vitriol And Olive Oil In Psudomonas Areoginosa Infected Burns In Experiental Rat Model. Asian J Anim Vet Adv. 2011;6:572-579. DOI: 10.3923/ajava.2011.572.579.
  13. Abdel-Hafez SMN, Rifaai RA, Abdelzaher WY. Possible protective effect of royal jelly against cyclophosphamide induced prostatic damage in male albino rats; a biochemical, histological and immuno-histo-chemical study. Biomed Pharmacother. 2017;90:15-23. DOI: 10.1016/j.biopha.2017.03.020. PMID: 28340377.
  14. El-Nekeety AA, El-Kholy W, Abbas NF, et al. Efficacy of royal jelly against the oxidative stress of fumonisin in rats. Toxicon. 2007;50:256-269. DOI: 10.1016/j.toxicon.2007.03.017. PMID: 17490698.
  15. Hazrati M, Mehrabani D, Japoni A, et al. Effect Of Honey On Healing Of Pseudomonas Aeruginosa Infected Burn Wounds In Rat. J Appl Anim Res. 2010;37:106-10. DOI: 10.1080/09712119.2010.9707117.
  16. Nejabat M, Astaneh AR, Eghtedari M, et al. Effect Of Honey In Pseudomonas Aeruginosa Induced Stromal Keratitis In Rabbits. J Appl Anim Res. 2009;35:33-36. DOI: 10.1080/09712119.2009.9706996.
  17. Ibrahim AAE-M. Immunomodulatory effects of royal jelly on aorta CD3, CD68 and eNOS expression in hypercholesterolaemic rats. J Basic Appl Zool. 2014;67:140-148. DOI: 10.1016/j.jobaz.2014.08.006
  18. Foaud MA, Kamel AH, Abd El-Monem DD. The protective effect of N-acetyl cysteine against carbon tetrachloride toxicity in rats. J Basic Appl Zool. 2018;79:1-13. DOI: 10.1186/s41936-018-0022-x.
  19. Cemek M, Aymelek F, Büyükokuroĝlu ME, et al. Protective potential of Royal Jelly against carbon tetrachloride induced-toxicity and changes in the serum sialic acid levels. Food Chem Toxicol. 2010;48:2827-2832. DOI: 10.1016/j.fct.2010.07.013. PMID: 20637822.
  20. Ganguly R, Kumar R, Pandey AK. Baicalin provides protection against fluoxetine-induced hepatotoxicity by modulation of oxidative stress and inflammation. World J Hepatol. 2022;14:729-743. DOI: 10.4254/wjh.v14.i4.729. PMID: 35646277.
  21. Maheswari E, Saraswathy GRL, Santhranii T. Hepatoprotective and antioxidant activity of N-acetyl cysteine in carbamazepine-administered rats. Indian J Pharmacol. 2014;46:211-215. DOI: 10.4103/0253-7613.129321. PMID: 24741196.
  22. Mostafa RE, El-Marasy SA, Abdel Jaleel GA, Bakeer RM. Protective effect of royal jelly against diclofenac-induced hepato-renal damage and gastrointestinal ulcerations in rats. Heliyon. 2020;6:e03330. DOI: 10.1016/j.heliyon.2020.e03330. PMID: 32025584.
  23. Fouzi M, Razmi N, Mehrabani D. The effect of Citrullus colocynthis on serum lipid profile and hepatic histology in CCl 4-induced liver injury rat model. Int J Nutr Sci. 2020;5:208-213. DOI: 10.30476/ijns.2020.88244.1094.
  24. Preskorn SH, Shah R, Neff M, et al. The potential for clinically significant drug-drug interactions involving the CYP 2D6 system: Effects with fluoxetine and paroxetine versus sertraline. J Psychiatr Pract. 2007;13:5-12. DOI: 10.1097/00131746-200701000-00002. PMID: 17242587.
  25. Mohamed Kamel GA, Harahsheh E, Hussein S. Mechanisms underlying the hepatoprotective effect of silymarin on fluoxetine-induced liver injury in rats: the implication of peroxisome proliferator–activated receptor-gamma (PPAR-γ). Comp Clin Pathol. 2022;31:689-698. DOI: 10.1007/s00580-022-03369-7.
  26. Beigi T, Safi A, Satvati M, et al. Protective role of ellagic acid and taurine against fluoxetine induced hepatotoxic effects on biochemical and oxidative stress parameters, histopathological changes, and gene expressions of IL-1β, NF-κB, and TNF-α in male Wistar rats. Life Sci. 2022;304:120679. DOI: 10.1016/j.lfs.2022.120679. PMID: 35662648.
  27. Jamhiri I, Zahri S, Mehrabani D, et al. The modulatory role of endogenous il-24/mda-7 in inflammatory response of human hepatic stellate cell (hsc), lx2. J Arak Univ Med Sci. 2018;20:13-21.
  28. Jamhiri I, Hosseini SY, Mehrabani D, et al. The pattern of il-24/mda-7 and its cognate receptors expression following activation of human hepatic stellate cells. Biomed Rep. 2017;7:173-178. DOI: 10.3892/br.2017.931. PMID: 28804632.
  29. Abdel-Salam OME, Sleem AA, Youness ER, etal. Bone marrow-derived stem cells protect against haloperidol-induced brain and liver damage in mice. Biomed Pharmacol J. 2018;11:11-22. DOI: 10.13005/bpj/1343.
  30. Goudarzi Z, Hoseini SE, Mehrabani D, et al. Change in blood chemistry, pro-inflammatory cytokines, and apoptotic genes following methamphetamine use in experimental rats. Periódico Tchê Química. 2020;17:1147-1159. DOI: 10.52571/ptq.v17.n36.2020.1163_periodico36_pgs_1147_1159.pdf.
  31. Crupi R, Gugliandolo E, Siracusa R, et al. N-acetyl-L-cysteine reduces Leishmania amazonensis-induced inflammation in BALB/c mice. BMC Vet Res. 2020;16:1-12. DOI: 10.1186/s12917-020-2234-9.
  32. Hamza RZ, Al-Eisa RA, El-Shenawy NS. Possible Ameliorative Effects of the Royal Jelly on Hepatotoxicity and Oxidative Stress Induced by Molybdenum Nanoparticles and/or Cadmium Chloride in Male Rats. Biology. 2022;11:450. DOI: 10.3390/biology11030450. PMID: 35336823.
  33. Yildirim S, KaradenIz A, Karakoç A, et al. Effects of royal jelly on liver paraoxonase activity in rats treated with cisplatin. Turk Med Sci. 2012;42:36-375. DOI: 10.3906/sag-1102-1373.
  34. Yi D, Hou Y, Wang L, et al. Dietary N-acetylcysteine supplementation alleviates liver injury in lipopolysaccharide-challenged piglets. Br J Nutr. 2014;111:46-54. DOI: 10.1017/S0007114513002171. PMID: 23829996.
  35. Abroudi M, Mehrabani D, Zare S, et al. In Vitro Assessment of Morphology, Proliferation, Apoptosis and Differential Potential of Dental Pulp Stem Cells, When Marijuana Is Added to Nutrients of Cell Culture Medium. Int J Nutr Sci. 2024;9:62-70. DOI: 10.30476/ijns.2024.101034.1288.
  36. Al-Geam MAI, Al-Shawi NN. Effects of Vitamin E and Q10 supplementation against doxorubicin-induced neurotoxicity in rats. Iraqi J Pharmaceutic Sci. 2018;27:24-31. DOI: 10.31351/vol27iss2pp24-31.
  37. Minegaki N, Koshizuka T, Hatasa K, et al. The C-Terminal Penta-Peptide Repeats of Major Royal Jelly Protein 3 Ameliorate the Progression of Inflammation in Vivo and in Vitro. Biological Pharmaceutical Bulletin. 2022;45(5):583589. DOI: 10.1248/bpb.b21-00922.
  38. Ahmad S, Campos MG, Fratini F, et al. New insights into the biological and pharmaceutical properties of royal jelly. Int J Mol Sci. 2020;21:382. DOI: 10.3390/ijms21020382. PMID: 31936187.
  39. Chen YF, You MM, Liu YC, et al. Potential protective effect of Trans-10-hydroxy-2-decenoic acid on the inflammation induced by Lipoteichoic acid. J Funct Foods. 2018;45:491-498. DOI: 10.1016/j.jff.2018.03.029
  40. Pourmobini H, Arababadi MK, Salahshoor MR, et al. The effect of royal jelly and silver nanoparticles on liver and kidney inflammation. Avicenna J Phytomed. 2021;11:218-223. DOI: 10.22038/AJP.2020.17045. PMID: 34046318.