Astaxanthin effect on apoptotic biomarkers in methotrexate-induced liver injury

Authors

  • Sarah Saad Hamdan Department of Pharmacology and Toxicology, Mustansiriyah University, Pharmacy College, Iraq
  • Yassir Mustafa Kamal Department of Pharmacology and Toxicology, Mustansiriyah University, Pharmacy College, Iraq
  • Huda Jaber Waheed Department of Pharmacology and Toxicology, Mustansiriyah University, Pharmacy College, Iraq

DOI:

https://doi.org/10.32947/ajps.v22i3.888

Keywords:

Methotrexate, hepatotoxicity, astaxanthin, caspase 9 and caspase 3.

Abstract

Methotrexate is used in the treatment of cancer, psoriasis, rheumatoid arthritis and several other disorders. It has a hepatotoxic potential side effect. Patients who have no access to alternative medications face a serious

 

challenge as a result. The current study aimed to assess the apoptotic potential of methotrexate on liver cells and evaluate the hepatoprotective activity of the potent antioxidant astaxanthin, by downregulation of apoptotic biomarkers caspase 9 and caspase 3.

A model of methotrexate-induced liver toxicity was employed on male rats. Thirty-six rats were divided into six groups; a negative control group, methotrexate induction group given (20 mg/kg) on day 13, three groups pretreated with astaxanthin in ascending doses (50, 75 and 100 mg/kg) for 14 days before methotrexate, and a conventional therapy group pretreated with silymarin (200mg/kg).

The use of methotrexate significantly increased liver tissue caspase 9 and caspase 3 compared to the negative control. On the other side, astaxanthin used in all three doses significantly normalized these biomarkers. This study revealed that since astaxanthin significantly decreased caspase 9 and caspase 3 that are involved in the apoptotic pathway, it could be used as pretreatment in patients treated with methotrexate to alleviate its hepatotoxicity.

References

Garcia-Cortes M, Robles-Diaz M, Stephens C, Ortega-Alonso A, Lucena MI, Andrade RJ. Drug induced liver injury: an update. Arch Toxicol [Internet]. 2020;94(10):3381–407. DOI: https://doi.org/10.1007/s00204-020-02885-1

- Zhou Y, Shen JX, Lauschke VM. Comprehensive evaluation of organotypic and microphysiological liver models for prediction of drug-induced liver injury. Front Pharmacol. 2019;10(SEP):1–22. DOI: https://doi.org/10.3389/fphar.2019.01093

- Said AM, Al-Khashali D, Al-Khateeb E. The hepatoprotective activity of Fenugreek seeds’ extract against carbon tetrachloride induced liver toxicity in rats. Al Mustansiriyah J Pharm Sci. 2011;9(1):94–103. DOI: https://doi.org/10.32947/ajps.v9i1.275

- Devarbhavi H, Aithal G, Treeprasertsuk S, Takikawa H, Mao Y, Shasthry SM, et al. Drug-induced liver injury: Asia Pacific Association of Study of Liver consensus guidelines. Hepatol Int [Internet]. 2021;15(2):258–82. DOI: https://doi.org/10.1007/s12072-021-10144-3

- Cronstein BN, Aune TM. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol [Internet]. 2020;16(3):145–54. DOI: https://doi.org/10.1038/s41584-020-0373-9

- Kim J, Kim Y, Choi J, Jung H, Lee K, Kang J, et al. Recapitulation of methotrexate hepatotoxicity with induced pluripotent stem cell-derived hepatocytes from patients with rheumatoid arthritis. Stem Cell Res Ther. 2018;9(1):1–15. DOI: https://doi.org/10.1186/s13287-018-1100-1

- Ebrahimi R, Sepand MR, Seyednejad SA, Omidi A, Akbariani M, Gholami M, et al. Ellagic acid reduces methotrexate-induced apoptosis and mitochondrial dysfunction via up-regulating Nrf2 expression and inhibiting the IĸBα/NFĸB in rats. DARU, J Pharm Sci. 2019;27(2):721–33. DOI: https://doi.org/10.1007/s40199-019-00309-9

- Mahmoud AM, Hussein OE, Hozayen WG, Bin-Jumah M, Abd El-Twab SM. Ferulic acid prevents oxidative stress, inflammation, and liver injury via upregulation of Nrf2/HO-1 signaling in methotrexate-induced rats. Environ Sci Pollut Res. 2020;27(8):7910–21. DOI: https://doi.org/10.1007/s11356-019-07532-6

- Ezhilarasan D. Hepatotoxic potentials of methotrexate: Understanding the possible toxicological molecular mechanisms. Toxicology [Internet]. 2021;458(162):152840. DOI: https://doi.org/10.1016/j.tox.2021.152840

- Soliman MM, Aldhahrani A, Alkhedaide A, Nassan MA, Althobaiti F, Mohamed WA. The ameliorative impacts of Moringa oleifera leaf extract against oxidative stress and methotrexate-induced hepato-renal dysfunction. Biomed Pharmacother [Internet].

- Kareem WA, Abdullah BH, Waheed HJ. Estimation Of Plasminogen Activator Inhibitor -1 And Some Biochemical Markers In A Sample Of Iraqi Patients With Liver Cirrhosis. Syst Rev Pharm. 2021;12(3):96–9.

- Alabbassi MG, Hussin SA-R, Ali SH, Alwakeel N. Prophylactic Effects of Melatonin in Lead Induced Toxicity in Rats. Al Mustansiriyah J Pharm Sci. 2009;6(1):157–73. DOI: https://doi.org/10.32947/ajps.v6i1.368

- Ambati RR, Moi PS, Ravi S, Aswathanarayana RG. Astaxanthin: Sources, extraction, stability, biological activities and its commercial applications - A review. Mar Drugs. 2014;12(1):128–52. DOI: https://doi.org/10.3390/md12010128

- Pan L, Wang H, Gu K. Nanoliposomes as vehicles for astaxanthin: Characterization, in vitro release evaluation and structure. Molecules. 2018;23(11). DOI: https://doi.org/10.3390/molecules23112822

- Gao L-J, Zhu Y-Q, Xu L. Mechanisms of protective effects of astaxanthin in nonalcoholic fatty liver disease. Hepatoma Res. 2021;7(30). DOI: https://doi.org/10.20517/2394-5079.2020.150

- Pereira CPM, Souza ACR, Vasconcelos AR, Prado PS, Name JJ. Antioxidant and anti-inflammatory mechanisms of action of astaxanthin in cardiovascular diseases (Review). Int J Mol Med. 2021;47(1):37–48. DOI: https://doi.org/10.3892/ijmm.2020.4783

- Luay R, Mustafa Y, Jaber H. Determination of endothelin-1 after treatment with rosuvastatin in induced hyperlipidemic rats. Int J Drug Deliv Technol. 2021;11(3):1054–7.

- Mshemish BAR, Al-Khazragy KA, AL-Nakaash MAI, Fatah WA. Effect of Silymarin against CAF protocol Hepatotoxicity. Al Mustansiriyah J Pharm Sci. 2011;9(1):52–62. DOI: https://doi.org/10.32947/ajps.v9i1.271

- Azzam A, Jiyad Z, O’Beirne J. Is methotrexate hepatotoxicity associated with cumulative dose? A systematic review and meta-analysis. Australas J Dermatol. 2021;62(2):130–40. DOI: https://doi.org/10.1111/ajd.13546

- Al Kury LT, Dayyan F, Shah FA, Malik Z, Khalil AAK, Alattar A, et al. Ginkgo biloba extract Protects against methotrexate-induced hepatotoxicity: A computational and pharmacological approach. Molecules. 2020;25(11). DOI: https://doi.org/10.3390/molecules25112540

- Pınar N, Kaplan M, Özgür T, Özcan O. Ameliorating effects of tempol on methotrexate-induced liver injury in rats. Biomed Pharmacother. 2018;102:758–64. DOI: https://doi.org/10.1016/j.biopha.2018.03.147

- Ali N, Rashid S, Nafees S, Hasan SK, Shahid A, Majed F, et al. Protective effect of Chlorogenic acid against methotrexate induced oxidative stress, inflammation and apoptosis in rat liver: An experimental approach [Internet]. Elsevier Ireland Ltd; 2017;272;80–91. DOI: https://doi.org/10.1016/j.cbi.2017.05.002

Downloads

Published

2022-10-24

How to Cite

Sarah Saad Hamdan, Yassir Mustafa Kamal, & Huda Jaber Waheed. (2022). Astaxanthin effect on apoptotic biomarkers in methotrexate-induced liver injury. Al Mustansiriyah Journal of Pharmaceutical Sciences, 22(3), 43–50. https://doi.org/10.32947/ajps.v22i3.888