Sıçanlarda Silimarinin Beyin Hasarı Üzerine Koruyucu Etkisi

Bu çalışmada silimarin’in sıçanlarda histolojik ve biyokimyasal parametrelerle valproik asite bağlı beyin hasarı üzerindeki olası koruyucu etkilerini değerlendirdik. Deney 21 Sprague Dawley erkek sıçan ile yapıldı. Sıçanlar üç gruba ayrıldı: grup 1 kontrol, grup 2 valproik asit ve grup 3 valproik asit + silimarin. Gruplara kontrol grubu dışında 14 gün boyunca 500 mg/kg/gün valproik asit ve 14 gün boyunca 100 mg/kg silimarin verildi. Valproik asit ile artmış serum glikoz, kolesterol, trigliserit ve kreatin kinaz BB seviyeleri, silimarin uygulaması ile tersine çevrildi. Ayrıca, valproik asitle beyin dokusunda artmış malondialdehit ve azalmış glutatyon düzeyleri, silimarin ile anlamlı önemli ölçüde baskılanmıştır. Valproik asit + silimarin grubunda oksidatif stres azaldı, antioksidan aktivite arttı ve valproik asit grubuna göre histopatolojik değişiklikler azaldı. Valproik asidin neden olduğu beyin hasarı, silimarin’in antioksidatif ve anti-apoptotik etkileri nedeniyle silimarin tedavisi ile azaltıldı. Silimarin, valproik asite bağlı beyin hasarının şiddetini azaltmak için yararlı olabilir.

Anahtar Kelimeler:

Beyin hasarı, Sıçan, Silimarin, Valproik asit

The Treatment Effect of Silymarin on Brain Damage in Rats

Bu çalışmada, silymarinin sıçanlarda histolojik ve biyokimyasal parametreler kullanarak valproik aside bağlı beyin hasarı üzerindeki olası koruyucu etkilerini araştırmayı amaçladık. Deney 21 Sprague Dawley erkek sıçan ile yapıldı. Sıçanlar üç gruba ayrıldı: grup 1; kontrol, grup 2; valproik asit, grup 3; valproik asit + silimarin. Gruplara kontrol grubu hariç 14 gün boyunca 500 mg / kg / gün valproik asit ve 14 gün boyunca 100 mg / kg sililmarin verildi. Valproik asit ile artan glukoz, kolesterol, trigliserit ve kreatin kinaz BB seviyeleri silimarin tedavisi ile tersine çevrilmiştir (p <0.05). Ayrıca, beyin dokusunda valproik asit ile artan malondialdehit ve azalan glutatyon seviyesi, silimarin tarafından önemli ölçüde baskılanmıştır (p <0.05). Histolojik olarak, valproik asit + silimarin grubunda beyin hasarı anlamlı derecede düşük olarak tespit edildi. Valproik asit + silimarin grubunda histopatolojik bulgular valproik asit grubuna göre anlamlı olarak azaldı (p < 0.05). Bu çalışmada silimarinin valproik aside bağlı beyin hasarı üzerinde iyileştirici etkisi olduğu görülmüştür. Bu anlamda çalışmamızın silimarin ve valproik asit ile çalışılacak diğer çalışmalar için faydalı olacağına inanıyoruz.

Keywords:

Brain damage, Rat, Silymarin, Valproic acid,

PDF

___

1. Abdelsalam HM, Samak MA, Alsemeh AE (2019). Synergistic therapeutic effects of Vitis vinifera extract and Silymarin on experimentally induced cardiorenal injury: The pertinent role of Nrf2. Biomed Pharmacother, 110, 37–46.
2. Agarwal NB, Agarwal NK, Mediratta PK, Sharma KK (2011). Effect of lamotrigine, oxcarbazepine and topiramate on cognitive functions and oxidative stress in PTZ-kindled mice. Seizure, 20(3), 257–62.
3. Ali NM, Mahmoud AAA, Mahmoud MF, El Fayoumi HM (2019). Glycyrrhizic acid and silymarin alleviate the neurotoxic effects of aluminum in rats challenged with fructose-induced insulin resistance: possible role of toll-like receptor 4 pathway. Drug Chem Toxicol, 42(2), 210-219.
4. Aktaş I, Armağan I (2019). Investigation of the positive effects of silymarin on valproic acid-induced liver damage in rats. AdıyamanÜni Sağlık Bilim, 5(2), 1445–1458.
5. Avci H, Epikmen ET, Ipek E, Tunca R, Birincioglu SS, Akşit H, et al. (2017). Protective effects of silymarin and curcumin on cyclophosphamide-induced cardiotoxicity. Exp Toxicol Pathol, 69(5), 317–27.
6. Beydilli H, Yilmaz N, Cetin ES, Topal Y, Celik OI, Sahin C, et al. (2015). Evaluation of the protective effect of silibinin against diazinon induced hepatotoxicity and free-radical damage in rat liver. Iran Red Crescent Med J, 17 (4), 1–7.
7. Bollino D, Balan I, Aurelian L (2015). Valproic acid induces neuronal cell death through a novel calpain-dependent necroptosis pathway. J Neurochem, 133(2), 174–186.
8. Borah A, Paul R, Choudhury S, Choudhury A, Bhuyan B, Das Talukdar A, et al. (2013). Neuroprotective potential of silymarin against CNS disorders: Insight into the pathways and molecular mechanisms of action. CNS Neurosci Ther, 19(11), 847–53.
9. Cárdenas-Rodríguez N, Coballase-Urrutia E, Rivera-Espinosa L, Romero-Toledo A, Sampieri AI, Ortega-Cuellar D, et al. (2013). Modulation of antioxidant enzymatic activities by certain antiepileptic drugs (valproic acid, oxcarbazepine, and topiramate): Evidence in humans and experimental models. Oxid Med Cell Longev, 2013, 598–493.
10. Chaudhary S, Parvez S (2018). Valproic acid induced neurotoxicological manifestations and its mitigation by melatonin in rat brain synaptosomes. Arch Med Res, 49(7), 441–450.
11. Crowley LV (1967). The reitman-frankel colorimetric transaminase procedure in suspected myocardial infarction. Clin Chem, 13(6), 482–7.
12. de Avelar CR, Pereira EM, de Farias Costa PR, de Jesus RP, de Oliveira LPM (2017). Effect of silymarin on biochemical indicators in patients with liver disease: Systematic review with meta-analysis. World J Gastroenterol, 23(27), 5004–5017.
13. Demirel Yılmaz B, Eren B, Sağır D, Eren Z, Başardı Gökçe A (2019). Stereological examination of curcumin’s effects on hippocampal damage caused by the anti-epileptic drugs phenobarbital and valproic acid in the developing rat brain. Acta Histochem, 121(4), 430–436.
14. Di Costanzo A, Angelico R (2019). Formulation strategies for enhancing the bioavailability of silymarin: The state of the art. Molecules, 24(11), 1–29.
15. Eckert M, Klumpp L, Huber S (2017). Cellular effects of the antiepileptic drug valproic acid in glioblastoma. Cell Physiol Biochem, 44(4), 1591–605.
16. Eissa N, Jayaprakash P, Azimullah S, Ojha SK, Al-Houqani M, Jalal FY, et al. (2018). The histamine H3R antagonist DL77 attenuates autistic behaviors in a prenatal valproic acid-induced mouse model of autism. Sci Rep, 8(1), 1–15.
17. El-Marasy SA, Abd-Elsalam RM, Ahmed-Farid OA (2018). Ameliorative effect of silymarin on scopolamine-induced dementia in rats. Open Access Maced J Med Sci, 6(7), 1215–24.
18. Emekli-Alturfan E, Alev B, Tunali S, Oktay S, Tunali-Akbay T, Ozturk LK, et al. (2015). Effects of edaravone on cardiac damage in valproic acid induced toxicity. Ann Clin Lab Sci, 45(2), 166–72.
19. Gabrielová E, Zholobenko AV, Bartošíková L, Nečas J, Modriansky M (2015). Silymarin constituent 2,3-dehydrosilybin triggers reserpine-sensitive positive inotropic effect in perfused rat heart. PLoS One, 10(9), 1–15.
20. Gynther M, Peura L, Vernerová M, Leppänen J, Kärkkäinen J, Lehtonen M, et al. (2016). Amino acid promoieties alter valproic acid pharmacokinetics and enable extended brain exposure. Neurochem Res, 41(10), 2797–809.
21. Katebi B, Mahdavimehr M, Meratan AA, Ghasemi A, Nemat-Gorgani M (2018). Protective effects of silibinin on insulin amyloid fibrillation, cytotoxicity and mitochondrial membrane damage. Arch Biochem Biophys, 659, 22–32.
22. Kumburovic I, Selakovic D, Juric T, Jovicic N, Mihailovic V, Stankovic JK, et al. (2019). Antioxidant effects of satureja hortensis L. attenuate the anxiogenic effect of cisplatin in rats. Oxid Med Cell Longev, 2019, 1–15.
23. Mahmoodi-Nesheli M, Alizadeh S, Solhi H, Mohseni J, Mahmoodi-Nesheli M (2018). Adjuvant effect of oral Silymarin on patients’ wound healing process caused by thermal injuries. Caspian J Intern Med, 9(4), 341–346.
24. Mostafa HE, Alaa-Eldin EA, El-Shafei DA, Abouhashem NS (2017). Alleviative effect of licorice on copper chloride-induced oxidative stress in the brain: biochemical, histopathological, immunohistochemical, and genotoxic study. Environ Sci Pollut Res Int, 24(22), 18585–18595.
25. Muthumani M, Prabu SM (2014). Silibinin potentially attenuates arsenic-induced oxidative stress mediated cardiotoxicity and dyslipidemia in rats. Cardiovasc Toxicol, 14(1), 83–97.
26. Nazıroğlu M, Yürekli, VA (2013). Effects of antiepileptic drugs on antioxidant and oxidant molecular pathways: Focus on trace elements. Cell Mol Neurobiol, 33(5), 589–99.
27. Neha, Kumar A, Jaggi AS, Sodhi RK, Singh N (2014). Silymarin ameliorates memory deficits and neuropathological changes in mouse model of high-fat-diet-induced experimental dementia. Naunyn Schmiedebergs Arch Pharmacol, 387(8), 777-87.
28. Palsamy P, Bidasee KR, Shinohara T (2014). Valproic acid suppresses Nrf2/Keap1 dependent antioxidant protection through induction of endoplasmic reticulum stress and Keap1 promoter DNA demethylation in human lens epithelial cells. Exp Eye Res, 121, 26–34.
29. Parlar A, Arslan SO, Doğan MF, Çam SA, Yalçin A, Elibol E (2018). The exogenous administration of CB2 specific agonist, GW405833, inhibits inflammation by reducing cytokine production and oxidative stress. Exp Ther Med, 16(6), 4900–908.
30. Placer ZA, Cushman LL, Johnson BC (1966). Estimation of product of lipid peroxidation (malonyl dialdehyde) in biochemical systems. Anal Biochem, 16(2), 359–64.
31. Rašković A, Stilinović N, Kolarović J, Vasović V, Vukmirović S, Mikov M (2011). The protective effects of silymarin against doxorubicin-induced cardiotoxicity and hepatotoxicity in rats. Molecules, 16(10), 8601–13.
32. Sedlak J, Lindsay RH (1968). Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem, 25(1), 192–205.
33. Sharma R, Rosenberg A, Bennett ER, Laskowitz DT, Acheson SK (2017). A blood-based biomarker panel to risk-stratify mild traumatic brain injury. PLoS One, 12(3), e0173798.
34. Streck EL, Amboni G, Scaini G, Di-Pietro PB, Rezin GT, Valvassori SS. et al. (1968). Brain creatine kinase activity in an animal model of mania. Life Sci, 82(7-8), 424-9.
35. Thakare VN, Aswar MK, Kulkarni YP, Patil RR, Patel BM (2017). Silymarin ameliorates experimentally induced depressive like behavior in rats: Involvement of hippocampal BDNF signaling, inflammatory cytokines and oxidative stress response. Physiol Behav, 179, 401–10.
36. Tong V, Teng XW, Chang TKH, Abbott FS (2005). Valproic cid I: Time course of lipid peroxidation biomarkers, liver toxicity, and valproic acid metabolite levels in rats. Toxicol Sci, 86(2), 427–435.
37. Wu H, Wang X, Gao J, Liang S, Hao Y, Sun C, et al. (2017). Fingolimod (FTY720) attenuates social deficits, learning and memory impairments, neuronal loss and neuroinflammation in the rat model of autism. Life Sci, 173, 43–54.
38. Yön B, Belviranlı M, Okudan N (2019). The effect of silymarin supplementation on cognitive impairment induced by diabetes in rats. J Basic Clin Physiol Pharmacol, 30(4), 1–9.
39. Zhu SY, Dong Y, Tu J, Zhou Y, Zhou XH, Xu B (2014). Silybum marianum oil attenuates oxidative stress and ameliorates mitochondrial dysfunction in mice treated with D-galactose. Pharmacogn Mag, 10, 92–9.
40. Zhou S, Lim LY, Chowbay B (2004). Herbal Modulation of P-Glycoprotein. Drug Metab Rev, 36(1), 7–104.