Ethics code: UPH/CEREMAD/REC/MM91/076


XML Print


Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:

Uahomo P, Isirima J. Biochemical and histological assessment of the hepatoprotective effects of Bryophyllum pinnatum leaf extract in Ketamine-induced liver toxicity in male Wistar rats. Journal of Research in Applied and Basic Medical Sciences 2025; 11 (1) :32-47
URL: http://ijrabms.umsu.ac.ir/article-1-370-en.html
Department of Pharmacology, Faculty of Basic Clinical Sciences, University of Port Harcourt, Choba, Rivers State, Nigeria , uahomoprecious1@gmail.com
Abstract:   (487 Views)
Background & Aims: Ketamine, a commonly used anesthetic and recreational drug, can induce liver toxicity through oxidative stress and hepatocellular damage. Bryophyllum pinnatum, traditionally used for liver-related ailments due to its hepatoprotective properties, has shown potential but remains underexplored for ketamine-induced toxicity. This study investigated the effects of B. pinnatum leaf extract on liver function biomarkers and histopathology in ketamine-induced hepatotoxicity in Wistar rats.
Materials & Methods: Sixty male Wistar rats were divided into six groups: normal control, ketamine-induced group (20 mg/kg, negative control), positive control (0.5 mg/kg risperidone), and three B. pinnatum-treated groups (50 mg/kg, 100 mg/kg, and 200 mg/kg). Serum levels of AST, ALT, ALP, GGT, and total protein were assessed, alongside histological analysis of liver tissues using hematoxylin and eosin staining. Statistical significance (p < 0.05) was determined using ANOVA and Dunnett’s post-hoc test.
Results: Ketamine significantly elevated liver enzyme levels (AST: 65.00 ± 2.89 U/L, ALT: 60.00 ± 2.89 U/L, ALP: 85.00 ± 2.89 U/L, GGT: 78.10 ± 3.09 U/L) and reduced total protein (6.07 ± 0.47 g/dL) compared to controls (AST: 27.67 ± 1.45 U/L, ALT: 22.33 ± 1.45 U/L, ALP: 37.67 ± 1.45 U/L, GGT: 34.27 ± 2.55 U/L; total protein: 7.40 ± 0.12 g/dL). Treatment with B. pinnatum normalized these biomarkers, with the 200 mg/kg dose showing the most significant effects (AST: 21.00 ± 2.08 U/L, ALT: 20.00 ± 5.77 U/L, ALP: 22.00 ± 3.06 U/L, GGT: 26.01 ± 3.11 U/L, total protein: 7.80 ± 0.12 g/dL). Histological findings indicated ketamine-induced hepatocyte damage was ameliorated by B. pinnatum in a dose-dependent manner, with marked improvements at 200 mg/kg.
Conclusion: B. pinnatum extract exhibits promising hepatoprotective effects against ketamine-induced liver toxicity, as evidenced by normalization of liver biomarkers and histological recovery. These preliminary findings in an animal model highlight its potential for therapeutic applications in liver disorders, warranting further investigation. 
Full-Text [PDF 1356 kb]   (120 Downloads)    
Type of Study: orginal article | Subject: General

References
1. Lent JK, Arredondo A, Pugh MA, Austin PN. Ketamine and treatment-resistant depression. AANA J. 2019;87(5):411-9. [PMID]
2. Smith-Apeldoorn SY, Veraart JK, Spijker J, Kamphuis J, Schoevers RA. Maintenance ketamine treatment for depression: a systematic review of efficacy, safety, and tolerability. Lancet Psychiatry 2022;9(11):907-21. [DOI:10.1016/S2215-0366(22)00317-0] [PMID]
3. Alnefeesi Y, Chen-Li D, Krane E, Jawad MY, Rodrigues NB, Ceban F, et al. Real-world effectiveness of ketamine in treatment-resistant depression: a systematic review & meta-analysis. J Psychiatr Res 2022;151:693-709. [DOI:10.1016/j.jpsychires.2022.04.037] [PMID]
4. Vestring S, Galuba V, Kern E, Voita S, Berens F, Nasiri D, et al. Ketamine in multiple treatment-resistant depressed inpatients: a naturalistic cohort study. J Affect Disord 2024;350:895-9. [DOI:10.1016/j.jad.2024.01.165] [PMID]
5. Cotter S, Wong J, Gada N, Gill R, Jones SC, Chai G, et al. Repeated or continuous medically supervised ketamine administration associated with hepatobiliary adverse events: a retrospective case series. Drug Saf 2021;44(12):1365-74. [DOI:10.1007/s40264-021-01120-9] [PMID] [PMCID]
6. Yoo N, Thomas S, Bender M, Cheng XJC. A case of hepatotoxicity induced by therapeutic ketamine use for sedation. Case Rep Crit Care 2024;2024:8366034. [DOI:10.1155/2024/8366034] [PMID] [PMCID]
7. Venâncio C, Antunes L, Félix L, Rodrigues P, Summavielle T, Peixoto F. Chronic ketamine administration impairs mitochondrial complex I in the rat liver. Life Sci 2013;93(12-14):464-70. [DOI:10.1016/j.lfs.2013.08.001] [PMID]
8. Robinson BL, Dumas M, Ali SF, Paule MG, Gu Q, Kanungo J. Mechanistic studies on ketamine-induced mitochondrial toxicity in zebrafish embryos. Neurotoxicol Teratol 2018;69:63-72. [DOI:10.1016/j.ntt.2017.12.005] [PMID] [PMCID]
9. Chen FH, Yu CF, Yang CL, Lin YC, Lin G, Wang CC, et al. Multimodal imaging reveals transient liver metabolic disturbance and sinusoidal circulation obstruction after a single administration of ketamine/xylazine mixture. Sci Rep 2020;10(1):3657. [DOI:10.1038/s41598-020-60347-1] [PMID] [PMCID]
10. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354(7):731-9. [DOI:10.1056/NEJMra052270] [PMID]
11. Abd El-Fattah LI, Ibrahim Ismail D. Histological study on the protective effect of green tea extract on the liver of rats exposed to ketamine. J Cytol Histol 2015;6:349. [DOI:10.4172/2157-7099.1000349]
12. Jones AL. Anatomy of the normal liver. In: Zakin D, Boyer TD, editors. Hepatology: a textbook of liver disease. 3rd ed. Philadelphia: WB Saunders; 1996. p. 3-32. [Google Scholar]
13. National Institute of Diabetes and Digestive and Kidney Diseases. LiverTox: clinical and research information on drug-induced liver injury. Bethesda, MD: National Institute of Diabetes and Digestive and Kidney Diseases. Ketamine. 2018. [PMID]
14. Bedir Z, Ozkaloglu Erdem KT, Ates I, Olmezturk Karakurt TC, Gursul C, Onk D, et al. Effects of ketamine, thiopental, and their combination on the rat liver: a biochemical evaluation. Adv Clin Exp Med 2022;31(3):285-92. [DOI:10.17219/acem/143573] [PMID]
15. Pappachan JM, Raj B, Thomas S, Hanna FW. Multiorgan dysfunction related to chronic ketamine abuse. Proc (Bayl Univ Med Cent) 2014;27(3):223-5. [DOI:10.1080/08998280.2014.11929117] [PMID] [PMCID]
16. Wong GL, Tam YH, Ng CF, Chan AW, Choi PC, Chu WC, et al. Liver injury is common among chronic abusers of ketamine. Clin Gastroenterol Hepatol 2014;12(10):1759-62.e1. [DOI:10.1016/j.cgh.2014.01.041] [PMID]
17. Niesters M, Martini C, Dahan A. Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol 2014;77(2):357-367. [DOI:10.1111/bcp.12094] [PMID] [PMCID]
18. Short B, Fong J, Galvez V, Shelker W, Loo CK. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry 2018;5(1):65-78. [DOI:10.1016/S2215-0366(17)30272-9] [PMID]
19. Strous JFM, Weeland CJ, van der Draai FA, Daams JG, Denys D, Lok A, Schoevers RA, Figee M. Brain changes associated with long-term ketamine abuse, a systematic review. Front Neuroanat 2022;16:795231. [DOI:10.3389/fnana.2022.795231] [PMID] [PMCID]
20. Fernandes JM, Cunha LM, Azevedo EP, Lourenço EMG, Pedrosa MF, Zucolotto SM. Kalanchoe laciniata and Bryophyllum pinnatum: an updated review about ethnopharmacology, phytochemistry, pharmacology and toxicology. Rev Bras Farmacogn 2019. [DOI:10.1016/j.bjp.2019.01.012]
21. Ghasi EC, Achukwu PU, Onyeanusi JC. Assessment of the medical benefits in the folklore use of Bryophyllum pinnatum leaf among the Igbos of Nigeria for the treatment of hypertension. Afr J Pharmacol 2011;5:83-92. [DOI:10.5897/AJPP10.309]
22. Afzal M, Kazmi I, Anwar F. Antineoplastic potential of Bryophyllum pinnatum Lam. on chemically induced hepatocarcinogenesis in rats. Pharmacogn Res 2013;5(4):247-253. [DOI:10.4103/0974-8490.118811] [PMID] [PMCID]
23. Bassey I, Udo E, Adesite S. Effect of crude aqueous leaves extract of Bryophyllum pinnatum on antioxidant status, blood glucose, lipid profile, liver and renal function indices in albino rats. Glob J Pure Appl Sci 2021;27:231-241. [DOI:10.4314/gjpas.v27i2.15]
24. Nneoyi-Egbe AF, Onyenweaku E, Akpanukoh A. Hepatoprotective activity of Bryophyllum pinnatum leaves (boiled extract) on albino Wistar rats - in vivo study. Int J Biochem Res Rev 2023;32(3):10-5. https://doi.org/10.9734/ijbcrr/2023/v32i3803 [DOI:10.9734/ijbcrr/2023/v32i3803.]
25. Fürer K, Raith M, Brenneisen R, Mennet M, Simões-Wüst AP, von Mandach U, Hamburger M, Potterat O. Two new flavonol glycosides and a metabolite profile of Bryophyllum pinnatum, a phytotherapeutic used in obstetrics and gynaecology. Planta Med 2013;79(16):1565-1571. [DOI:10.1055/s-0033-1350808] [PMID]
26. Elufioye TO, Olusola DM, Oyedeji AO. Correlation of total phenolic, flavonoid and tannin content of Bryophyllum pinnatum (Lam.) (Crassulaceae) extract with the antioxidant and anticholinesterase activities. Pharmacogn J 2019;11(5). [DOI:10.5530/pj.2019.11.158]
27. Ogidigo JO, Anosike CA, Joshua PE, Ibeji CU, Ekpo DE, Nwanguma BC, et al. UPLC-PDA-ESI-QTOF-MS/MS fingerprint of purified flavonoid enriched fraction of Bryophyllum pinnatum; antioxidant properties, anticholinesterase activity and in silico studies. Pharm Biol 2021;59(1):444-456. [DOI:10.1080/13880209.2021.1913189] [PMID] [PMCID]
28. Pal S, Chaudhuri AKN. Studies on the anti-ulcer activity of a Bryophyllum pinnatum leaf extract in experimental animals. J Ethnopharmacol 1991;33:97-102. [DOI:10.1016/0378-8741(91)90168-D] [PMID]
29. Ojewole JA. Antinociceptive, anti-inflammatory and antidiabetic effects of Bryophyllum pinnatum (Crassulaceae) leaf aqueous extract. J Ethnopharmacol 2005;99(1):13-19. [DOI:10.1016/j.jep.2005.01.025] [PMID]
30. Afzal M, Guypta G, Kazmi I, Rahman M, Afzal O, Alam J. Anti-inflammatory and analgesic potential of a novel steroidal derivative from Bryophyllum pinnatum. Fitoterapia 2012;83:848-853. [DOI:10.1016/j.fitote.2012.03.013] [PMID]
31. Parthasarathy M, Evan Prince S. The potential effect of phytochemicals and herbal plant remedies for treating drug-induced hepatotoxicity: a review. Mol Biol Rep 2021;48(5):4767-4788. [DOI:10.1007/s11033-021-06444-4] [PMID]
32. Hosomi JK, Facina ADS, Simões MJ, Nakamura MU. Effects of Bryophyllum pinnatum administration on Wistar rat pregnancy: biochemical and histological aspects. Complement Med Res 2022;29(1):35-42. [DOI:10.1159/000517508] [PMID]
33. Gupta S, Banerjee R. Radical scavenging potential of phenolics from Bryophyllum pinnatum (Lam.) Oken. Prep Biochem Biotechnol 2011;41(3):305-319. [DOI:10.1080/10826068.2010.541314] [PMID]
34. Bhandari R, Gyawali S, Aryal N, Gaire D, Paudyal K, Panta A, et al. Evaluation of phytochemical, antioxidant, and memory-enhancing activity of Garuga pinnata Roxb. bark and Bryophyllum pinnatum (Lam) Oken. leaves. Sci World J 2021;2021:6649574. [DOI:10.1155/2021/6649574] [PMID] [PMCID]
35. Pandey A, Tripathi S. Concept of standardization, extraction and pre-phytochemical screening strategies for herbal drug. J Pharmacogn Phytochem 2014;2(5):115-119. [Google Scholar]
36. Das K, Tiwari RKS, Shrivastava DK. Techniques for evaluation of medicinal plant products as antimicrobial agent: current methods and future trends. J Med Plants Res 2010;4(2):104-111. [Google Scholar]
37. Monte AS, de Souza GC, McIntyre RS, et al. Prevention and reversal of ketamine-induced schizophrenia-related behavior by minocycline in mice: possible involvement of antioxidant and nitrergic pathways. J Psychopharmacol 2013;27(11):1032-1043. [DOI:10.1177/0269881113503506] [PMID]
38. Ben-Azu B, Aderibigbe AO, Ajayi AM, Iwalewa EO. Neuroprotective effects of the ethanol stem bark extracts of Terminalia ivorensis in ketamine-induced schizophrenia-like behaviors and oxidative damage in mice. Pharm Biol 2016;54(12):2871-2879. [DOI:10.1080/13880209.2016.1190382] [PMID]
39. Salahdeen HM, Yemitan OK. Neuropharmacological effects of aqueous leaf extract of Bryophyllum pinnatum in mice. Afr J Biomed Res 2006;9:101-107. [DOI:10.4314/ajbr.v9i2.48782]
40. Bowen RA, Remaley AT. Interferences from blood collection tube components on clinical chemistry assays. Biochem Med 2014;24(1):31-44. [DOI:10.11613/BM.2014.006] [PMID] [PMCID]
41. Brinc D, Chan MK, Venner AA, Pasic MD, Colantonio D, Kyriakopolou L, et al. Long-term stability of biochemical markers in pediatric serum specimens stored at −80°C: A CALIPER Substudy. Clin Biochem 2012;45(10-11):816-26. [DOI:10.1016/j.clinbiochem.2012.03.029] [PMID]
42. Tietz NW. Clinical Guide to Laboratory Tests. 2nd ed. Philadelphia: W.B. Saunders Co.; 1990. p. 566. [Google Scholar]
43. Zheng K, Wu L, He Z, Yang B, Yang Y. Measurement of the total protein in serum by biuret method with uncertainty evaluation. Measurement. 2017;112:16-21. https://doi.org/10.1016/j.measurement.2017.08.013 [DOI:10.1016/j.measurement.2017.08.013.]
44. Baker JR. Cytological Technique. 2nd ed London: Methuen; 1945. [URL]
45. Isirima JC, Uahomo PO. Acalypha wilkesiana exhibits antihyperglycemic potentials and ameliorates damages to pancreas and spleen of diabetic rat model. Saudi J Biomed Res 2023;8(7):83-94. [DOI:10.36348/sjbr.2023.v08i07.001]
46. Giannini EG, Testa R, Savarino V. Liver enzyme alteration: a guide for clinicians. CMAJ 2005;172(3):367-79. https://doi.org/10.1503/cmaj.1040752 [DOI:10.1503/cmaj.1040752.] [PMID] [PMCID]
47. Lin JW, Lin YC, Liu JM, et al. Norketamine, the Main Metabolite of Ketamine, Induces Mitochondria-Dependent and ER Stress-Triggered Apoptotic Death in Urothelial Cells via a Ca2+-Regulated ERK1/2-Activating Pathway. Int J Mol Sci 2022;23(9):4666. [DOI:10.3390/ijms23094666] [PMID] []
48. Hall P, Cash J. What is the real function of the liver 'function' tests?. Ulster Med J 2012;81(1):30-6. [PMID]
49. Kalkan Y, Tomak Y, Altuner D, Tumkaya L, Bostan H, et al. Hepatic effects of ketamine administration for 2 weeks in rats. Hum Exp Toxicol 2014;33(1):32-40. https://doi.org/10.1177/0960327112472990 [DOI:10.1177/0960327112472990avali] [PMID]
50. Azirak S, Bilgic S, Tastemir Korkmaz D, Guvenc AN, Kocaman N, Ozer MK. The protective effect of resveratrol against risperidone-induced liver damage through an action on FAS gene expression. Gen Physiol Biophys 2019;38(3):215-25. https://doi.org/10.4149/gpb_2018045 [DOI:10.4149/gpb_2018045.] [PMID]
51. Bhandari R, Gyawali S, Aryal N, et al. Evaluation of Phytochemical, Antioxidant, and Memory-Enhancing Activity of Garuga pinnata Roxb. Bark and Bryophyllum pinnatum (Lam) Oken. Leaves. ScientificWorldJournal 2021;2021:6649574. [DOI:10.1155/2021/6649574] [PMID] [PMCID]
52. Robinson BL, Dumas M, Ali SF, Paule MG, Gu Q, Kanungo J. Mechanistic studies on ketamine-induced mitochondrial toxicity in zebrafish embryos. Neurotoxicol Teratol 2018;69:63-72. doi:10.1016/j.ntt.2017.12.005 [DOI:10.1016/j.ntt.2017.12.005] [PMID] [PMCID]
53. Ngobidi KC, Igbokwe GE, Ajayi A, Otuchristian O, Omoboyowa DA, Adindu C. Hepato-protective effect of ethanol leaf extract of Bryophyllum pinnatum on paracetamol induce hepatitis albino rats. 2016. Google Scholar. [URL]
54. Anosike CA, Mokwunye SU, Okpashi VE, Abonyi O. Modulatory effects of Bryophyllum pinnatum leaves extract on peroxidation indices of CCl₄-induced hepatotoxicity in Wistar albino rats. Am J Pharmacol Toxicol 2017;12(3):62-67. https://doi.org/10.3844/ajptsp.2017.62.67 [DOI:10.3844/ajptsp.2017.62.67.]
55. Uahomo PO, Isirima JC. Attenuating ketamine-induced nephrotoxicity with Bryophyllum pinnatum extract: Biochemical and histological investigation. J Complement Altern Med Res 2025;26(1):21-36. https://doi.org/10.9734/jocamr/2025/v26i1612 [DOI:10.9734/jocamr/2025/v26i1612.]
56. Díaz-Juárez JA, Hernández-Muñoz R. Rat liver enzyme release depends on blood flow-bearing physical forces acting in endothelium glycocalyx rather than on liver damage. Oxid Med Cell Longev 2017;2017:1360565. https://doi.org/10.1155/2017/1360565 [DOI:10.1155/2017/1360565.] [PMID] [PMCID]
57. Vieta E, Herraiz M, Fernández A, Gastó C, Benabarre A, Colom F, et al. Efficacy and safety of risperidone in the treatment of schizoaffective disorder: initial results from a large, multicenter surveillance study. Group for the Study of Risperidone in Affective Disorders (GSRAD). J Clin Psychiatry 2001;62(8):623-30. https://doi.org/10.4088/JCP.v62n0809 [DOI:10.4088/jcp.v62n0809.] [PMID]
58. Sajatovic M, Subramoniam M, Fuller MA. Risperidone in the treatment of bipolar mania. Neuropsychiatr Dis Treat 2006;2(2):127-38. https://doi.org/10.2147/nedt.2006.2.2.127 [DOI:10.2147/nedt.2006.2.2.127.] [PMID] [PMCID]

Add your comments about this article : Your username or Email:
CAPTCHA

Send email to the article author


Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

© 2025 CC BY-NC 4.0 | Journal of Research in Applied and Basic Medical Sciences

Designed & Developed by : Yektaweb