Carvacrol Ameliorates Cisplatin-Induced Cardiotoxicity By Regulating Notch/Hes1 Signaling Pathway, Oxidative Stress and Cell Death In Rat Cardiac Tissue

Abstract

Cisplatin is one of the most active cytotoxic agents used mainly in the treatment of solid tumors. High doses and long-term use of Cisplatin are known to cause cardiotoxicity. In recent years, the antiapoptotic and antioxidant effects of Carvacrol in cardiovascular diseases have attracted attention. In this study, the effects of Carvacrol on Cisplatin-induced cardiotoxicity in a rat model were investigated using biochemical and histological methods. Twenty-eight rats were divided into 4 groups: 1. Control group, 2. Carvacrol group, 3. Cisplatin group, 4. Cisplatin + Carvacrol group. The expression of antioxidant enzymes, proinflammatory cytokines, apoptotic, and autophagic proteins was examined in heart tissue obtained from rats sacrificed after the last drug administration. Additionally, heart tissue was evaluated histopathologically. Cisplatin has been observed to cause oxidative stress and inflammatory damage in animal heart tissue. Carvacrol administration significantly increased antioxidant enzyme (superoxide dismutase and glutathione peroxidase) activities while suppressing inflammatory markers (NF-κB, TNF-α, IL-1β). Additionally, Cisplatin induced apoptotic (caspase-3, Bax, Bcl-2) and autophagic (Beclin-1, LC3A, LC3B) markers. It has been determined that carvacrol can protect heart tissues from the destructive effects of cisplatin by exerting anti-apoptotic and anti-autophagic effects. The expression levels of Notch1 and Hes1, which were decreased by cisplatin administration, were upregulated after administration of Carvacrol. H&E staining results showed that Carvacrol preserved myocardial tissue integrity. In conclusion, Carvacrol showed a cardioprotective effect against cisplatin-induced cardiotoxicity.

Keywords

• Cisplatin
• Carvacrol
• Cardiac Tissue
• Oxidative Stress
• Apoptosis
• Rat

Karvakrol Sıçan Kalp Dokusunda Notch/Hes1 Sinyal Yolunu, Oksidatif Stresi ve Hücre Ölümünü Düzenleyerek Sisplatin Kaynaklı Kardiyotoksisiteyi İyileştirir

Abstract

Sisplatin esas olarak katı tümörlerin tedavisinde kullanılan en aktif sitotoksik ajanlardan biridir. Sisplatin’in yüksek doz ve uzun süreli kullanımı kardiyotoksisiteye neden olduğu bilinmektedir. Son yıllarda kardiyovasküler hastalıklarda Karvakrol’ün antiapoptotik ve antioksidan etkileri ilgi görmüştür. Bu çalışmada, bir sıçan modelinde Karvakrol’ün Sisplatin kaynaklı kardiyotoksisite üzerindeki etkileri biyokimyasal ve histolojik yöntemler kullanılarak araştırılmıştır. Yirmi sekiz sıçan 4 gruba ayrıldı: 1. kontrol grubu, 2. Karvakrol grubu, 3. Sisplatin grubu, 4. Sisplatin + Karvakrol grubu. Son ilaç uygulamasından sonra öldürülen sıçanlardan elde edilen kalp dokusunda antioksidan enzimlerin, proinflamatuar sitokinlerin, apoptotik ve otofajik proteinlerin ekspresyonu incelenmiştir. Ayrıca kalp dokusu histopatolojik olarak değerlendirilmiştir. Sisplatin'in hayvanların kalp dokusunda oksidatif strese ve inflamatuar hasara neden olduğu gözlenmiştir. Karvakrol uygulamasının antioksidan enzim (süperoksit dismutaz ve glutatyon peroksidaz) aktivitelerini önemli ölçüde artırırken, inflamatuar belirteçleri (NF-κB, TNF-α, IL-1β) baskıladı. Ayrıca Sisplatin’in apoptotik (caspase-3, Bax, Bcl-2) ve otofajik (Beclin-1, LC3A, LC3B) belirteçleri indükledi. Karvakrol’ün ise anti-apoptotik ve anti-otofajik etki göstererek kalp dokularını Sisplatin’in yıkıcı etkisinden koruyabildiği belirlenmiştir. Sisplatin uygulaması ile azalmış Notch1 ve Hes1 ekspresyon seviyeleri Karvakrol uygulamasından sonra düzenlenmiştir. H&E boyama sonuçları Karvakrol’ün miyokardiyal doku bütünlüğünü koruduğunu göstermiştir. Sonuç olarak, Karvakrol Sisplatin kaynaklı kardiyotoksisiteye karşı kardiyoprotektif bir etki gösterdi.

Keywords

• Sisplatin
• Karvakrol
• Kardiyak Doku
• Oksidatif Stres
• Apoptozis
• Sıçan

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