Investigation of the positive effects of silymarin on valproic acid-induced liver damage in rats

Year 2019, Volume: 5 Issue: 2, 1445 - 1458, 15.08.2019

İbrahim Aktaş , İlkay Armağan

https://doi.org/10.30569/adiyamansaglik.568226

Cited By: 1

Abstract

Purpose: In this study, we
evaluated the potential hepatoprotective effects of silymarin on valproic
acid-induced liver injury by histological and biochemical parameters in rat
liver.

Method:Experimental procedures
were performed on 21 male Sprague Dawley rats. Rats were divided into three
groups: group 1, control; group 2, valproic acid; group 3, valproic acid +
silymarin. The groups were administered 500 mg/kg/day valproic acidand 100
mg/kg/daysilymarin for 14 days, except control group.

Results:Silymarin treatment decreased
the levels of serumgamma glutamyl transferase, alanine amino transferase, aspartate
aminotransferase and increreased serum albumin levelssignificantly (p
<0.05). In addition, increased amount of malondialdehyde and decreased
levels of glutathione with valproic acid were significantly suppressed by
silymarin in liver tissue (p <0.05). The combination of silymarinwith valproic
acid reduced loss of body weight in the present study. Histologically, the
extent of liver damage was significantly lower in the valproic acid+silymarin
group (p<0.005). Oxidative stress was decreased, antioxidant activity was
increased and histopathological changes were reduced in the valproic acid + silymarin
group compared to the valproic acid group.

Conclusion:This study revealed that
the liver injury induced by valproic acid was attenuated with silymarin
administration. Silymarincan protect rat liver against valproic acid induced
injury by its anti-oxidative effect,
and might be useful for reducing the severity of liver injury.

Keywords

valproic acid, silymarin, liver injury, rat

Silimarinin, ratlarda valproik asitin indüklediği karaciğer hasarı üzerine olumlu etkilerinin araştırılması

Abstract

Amaç:Bu çalışmada; valproik asit kaynaklı ratlarda
karaciğer hasarına karşı silimarin'in olası hepatoprotektif etkilerini
histolojik ve biyokimyasal değerlendirmeler kullanarak araştırmayı amaçladık.

Gereç ve yöntemler:Deneysel işlemler, 21 adet Sprague
Dawley sıçanı üzerinde gerçekleştirildi. Sıçanlar üç gruba ayrıldı: grup 1,
kontrol; grup 2, valproik asit; grup 3, valproik asit + silimarin. Gruplara,
kontrol grubu hariç 500 mg/kg/gün valproik asit ve 100 mg/kg/gün silimarin 14
gün  uygulandı.

Bulgular:Valproik asitile artan serum gama glutamil transferaz,
alanin amino transferaz, aspartat aminotransferaz ve azalan serum albumin
seviyesi silimarin tedavisi ile tersine çevrildi (p<0.05). Ek olarak,
karaciğer dokusunda valproik asit ile malondialdehit seviyesinin artması ve glutatyon
seviyesinin azalması, silimarin tarafından önemli ölçüde baskılandı (p<0.05).
Silimarin'in,valproik asit ile kombinasyonu bu çalışmada vücut ağırlığı kaybını
azaltmıştır. Histolojik olarak, valproik asit + silimarin grubunda karaciğer
hasarının derecesi anlamlı olarak dah düşük bulundu (p <0.005). Valproik
asit + silimarin grubunda; valproik asit grubuna göre oksidatif streste azalma,
antioksidan aktivitede artışve histopatolojik değişikliklerde azalma kaydedildi.

Sonuç:Bu çalışma valproik asit'in indüklediği karaciğer
hasarının silimarin uygulaması ile azaldığını ortaya konuldu. Silimarin, sıçan
karaciğerini anti-oksidatif etkisi ile valproik asit kaynaklı hasara karşı
koruyabilir ve karaciğer hasarının boyutunu azaltmak için faydalı olabilir.

Keywords

Valproroik asit, silmarin, karaciğer, sıçan

References

• 1. Semmler A, Frisch C, Bleul C, Smith D, Bigler L, Prost J-C, et al. Intrauterine valproate exposure is associated with alterations in hippocampal cell numbers and folate metabolism in a rat model of valproate teratogenicity. Seizure [Internet]. 2017 Mar [cited 2019 May 21];46:7–12. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28212902
• 2. Kudin AP, Mawasi H, Eisenkraft A, Elger CE, Bialer M, Kunz WS. Mitochondrial Liver Toxicity of Valproic Acid and Its Acid Derivatives Is Related to Inhibition of α-Lipoamide Dehydrogenase. Int J Mol Sci [Internet]. 2017 Sep 6 [cited 2019 May 21];18(9). Available from: http://www.ncbi.nlm.nih.gov/pubmed/28878165
• 3. Ahangar N, Naderi M, Noroozi A, Ghasemi M, Zamani E, Shaki F. Zinc Deficiency and Oxidative Stress Involved in Valproic Acid Induced Hepatotoxicity: Protection by Zinc and Selenium Supplementation. Biol Trace Elem Res. 2017 Sep;179(1):102–9.
• 4. Holland KD. Efficacy, pharmacology, and adverse effects of antiepileptic drugs. Neurol Clin. 2001 May;19(2):313–45.
• 5. Tong V, Teng XW, Chang TKH, Abbott FS. Valproic Acid I: Time Course of Lipid Peroxidation Biomarkers, Liver Toxicity, and Valproic Acid Metabolite Levels in Rats. Toxicol Sci. 2005 Aug;86(2):427–35.
• 6. Graf W, Oleinik O, Glauser T, Maertens P, Eder D, Pippenger C. Altered Antioxidant Enzyme Activities in Children with a Serious Adverse Experience Related to Valproic Acid Therapy. Neuropediatrics. 1998 Aug;29(04):195–201.
• 7. El-Mowafy AM, Katary MM, Pye C, Ibrahim AS, Elmarakby AA. Novel molecular triggers underlie valproate-induced liver injury and its alleviation by the omega-3 fatty acid DHA: role of inflammation and apoptosis. Heliyon. 2016 Jul;2(7):e00130.
• 8. Gynther M, Peura L, Vernerová M, Leppänen J, Kärkkäinen J, Lehtonen M, et al. Amino Acid Promoieties Alter Valproic Acid Pharmacokinetics and Enable Extended Brain Exposure. Neurochem Res. 2016 Oct;41(10):2797–809.
• 9. Genotoxity evaluation in female patients on valproic. Vol. 5, Eastern Journal of Medicine.
• 10. Sokar SS, El-Sayad ME-S, Ghoneim ME-S, Shebl AM. Combination of Sitagliptin and Silymarin ameliorates liver fibrosis induced by carbon tetrachloride in rats. Biomed Pharmacother. 2017 May;89:98–107.
• 11. Sayın FK, Kübra F. Silybum marianum ekstresinin yüksek yağlı diyetle beslenen ratlarda insülin rezistansı, karaciğer fonksiyonları, lipit düzeyleri ve leptin seviyesi üzerine etkilerinin araştırılması. 2012;
• 12. Beydilli H, Yilmaz N, Cetin ES, Topal Y, Celik OI, Sahin C, et al. Evaluation of the protective effect of silibinin against diazinon induced hepatotoxicity and free-radical damage in rat liver. Iran Red Crescent Med J. 2015 Apr;17(4):e25310.
• 13. Abdel-Dayem MA, Elmarakby AA, Abdel-Aziz AA, Pye C, Said SA, El-Mowafy AM. Valproate-induced liver injury: modulation by the omega-3 fatty acid DHA proposes a novel anticonvulsant regimen. Drugs R D. 2014 Jun;14(2):85–94.
• 14. Crowley L V. The Reitman-Frankel Colorimetric Transaminase Procedure in Suspected Myocardial Infarction. Clin Chem. 1967;13(6).
• 15. Parlar A, Arslan SO, Doğan MF, Çam SA, Yalçin A, Elibol E, et al. The exogenous administration of CB2 specific agonist, GW405833, inhibits inflammation by reducing cytokine production and oxidative stress. Exp Ther Med [Internet]. 2018 Dec [cited 2019 May 18];16(6):4900–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30542446
• 16. Placer ZA, Cushman LL, Johnson BC. Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal Biochem. 1966 Aug;16(2):359–64.
• 17. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem. 1968 Jan;25:192–205.
• 18. Hepatoprotective Herbal Drug, Silymarin From Experimental Pharmacology to Clinical Medicine - Redorbit.
• 19. Lee M-H, Hong I, Kim M, Lee BH, Kim J-H, Kang K-S, et al. Gene expression profiles of murine fatty liver induced by the administration of valproic acid. Toxicol Appl Pharmacol. 2007 Apr;220(1):45–59.
• 20. Powell-Jackson PR, Tredger JM, Williams R. Hepatotoxicity to sodium valproate: a review. Gut. 1984 Jun;25(6):673–81.
• 21. de Avelar CR, Pereira EM, de Farias Costa PR, de Jesus RP, de Oliveira LPM. Effect of silymarin on biochemical indicators in patients with liver disease: Systematic review with meta-analysis. World J Gastroenterol. 2017 Jul;23(27):5004–17.
• 22. Pourahmad J, Eskandari MR, Kaghazi A, Shaki F, Shahraki J, Fard JK. A new approach on valproic acid induced hepatotoxicity: Involvement of lysosomal membrane leakiness and cellular proteolysis. Toxicol Vitr. 2012 Jun;26(4):545–51.
• 23. Malekinejad H, Rokhsartalab-Azar S, Hassani-Dizaj S, Alizadeh-Fanalou S, Rezabakhsh A, Amniattalab A. Effects of silymarin on the pharmacokinetics of atorvastatin in diabetic rats. Eur J Drug Metab Pharmacokinet. 2014 Dec;39(4):311–20.
• 24. Younis T, Khan MR, Sajid M. Protective effects of Fraxinus xanthoxyloides (Wall.) leaves against CCl4 induced hepatic toxicity in rat. BMC Complement Altern Med. 2016 Oct;16(1):407.
• 25. Kidd P, Head K. A review of the bioavailability and clinical efficacy of milk thistle phytosome: a silybin-phosphatidylcholine complex (Siliphos). Altern Med Rev. 2005 Sep;10(3):193–203.
• 26. Kandimalla R, Dash S, Bhowal AC, Kalita S, Talukdar NC, Kundu S, et al. Glycogen-gold nanohybrid escalates the potency of silymarin. Int J Nanomedicine. 2017;12:7025–38.
• 27. El-Mowafy AM, Abdel-Dayem MA, Abdel-Aziz A, El-Azab MF, Said SA. Eicosapentaenoic acid ablates valproate-induced liver oxidative stress and cellular derangement without altering its clearance rate: Dynamic synergy and therapeutic utility. Biochim Biophys Acta - Mol Cell Biol Lipids. 2011 Jul;1811(7–8):460–7.
• 28. Goda K, Saito K, Muta K, Kobayashi A, Saito Y, Sugai S. Ether-phosphatidylcholine characterized by consolidated plasma and liver lipidomics is a predictive biomarker for valproic acid-induced hepatic steatosis. J Toxicol Sci. 2018;43(6):395–405.
• 29. Altınok-Yipel F, Ozan Tekeli İ, Özsoy ŞY, Güvenç M, Kaya A, Yipel M. Hepatoprotective Activity of Linalool in Rats Against Liver Injury Induced by Carbon Tetrachloride. Int J Vitam Nutr Res. 2019 Apr;1–7.