Protective Effects of Esculetin at two Different Doses on Oxidative Stress, Inflammation, and Fibrotic Changes in AlCl₃-Induced Cardiotoxicity in Rats

Öz

Objective: Aluminum chloride (AlCl₃) is an environmental toxicant that promotes cardiotoxicity primarily by inducing oxidative stress and inflammatory responses. Esculetin (ESC), which is a naturally occurring coumarin derivative, possesses antioxidant, anti-inflammatory, and antifibrotic activities. This study evaluated the protective effects of ESC against AlCl₃-induced cardiotoxicity, with a focus on dose-related responses. Methods: 35 male Wistar albino rats were randomly assigned to five experimental groups (n=7 per group): Control, Vehicle, AlCl₃ (10 mg/kg), AlCl₃ + ESC50 (50 mg/kg), and AlCl₃ + ESC100 (100 mg/kg). All experimental treatments were administered orally once daily throughout the 14-day study period. Cardiac tissue levels of malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) were determined to assess oxidative stress. Tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) were measured to evaluate the inflammatory response. Histopathological changes and the immunoreactivity of inducible nitric oxide synthase (iNOS) and alpha-smooth muscle actin (α-SMA) were also evaluated. Results: AlCl₃ exposure led to increased MDA levels and decreased GSH levels, with reduced SOD and CAT activities in heart tissue (P<0.01). ESC treatment significantly reversed these alterations in both dose groups (P<0.01). Furthermore, TNF-α and IL-1β levels were significantly reduced in the ESC-treated groups compared with the AlCl₃ group (P<0.01). Histopathological examination revealed less myocardial damage in the ESC-treated groups, whereas immunohistochemical analysis showed reduced iNOS and α-SMA immunoreactivity. The protective effects were greater in the 100 mg/kg ESC-treated group. Conclusion: ESC mitigates AlCl₃-induced cardiotoxicity through modulation of oxidative stress and inflammatory responses, improvement of histological findings, and influence on profibrotic alterations. Protective effects were observed with both ESC doses, with generally greater improvements in the higher-dose group.

Anahtar Kelimeler

• Aluminum chloride
• esculetin
• cardiotoxicity
• inflammation
• oxidative stress

Destekleyen Kurum

This work was supported by the Karabük University Scientific Research Fund [KBÜBAP-25-DS-191].

Etik Beyan

All experimental methods involving live animals used in the current study were approved by the Karabük University Local Ethics Committee (Approval number: 2025 /11-38).

Ratlarda AlCl₃ ile İndüklenen Kardiyotoksisitede İki Farklı Dozda Uygulanan Eskuletinin Oksidatif Stres, İnflamasyon ve Fibrotik Değişiklikler Üzerindeki Koruyucu Etkileri

Öz

Amaç: Alüminyum klorür (AlCl₃), başlıca oksidatif stres ve inflamasyon aracılığıyla kardiyotoksisiteye neden olan çevresel bir toksik ajandır. Doğal bir kumarin türevi olan eskületin (ESC), antioksidan, antiinflamatuar ve antifibrotik özellikler göstermektedir. Bu çalışmada, ESC’nin AlCl₃ ile indüklenen kardiyotoksisite üzerindeki koruyucu etkileri, dozla ilişkili yanıtlar açısından değerlendirilmiştir. Yöntemler: 35 adet erkek Wistar albino sıçan beş gruba ayrıldı (n=7): kontrol, vehicle, AlCl₃ (10 mg/kg), AlCl₃ + ESC50 (50 mg/kg) ve AlCl₃ + ESC100 (100 mg/kg). Tüm uygulamalar 14 gün boyunca günde bir kez oral yolla gerçekleştirildi. Kalp dokusunda malondialdehit (MDA), indirgenmiş glutatyon (GSH), süperoksit dismutaz (SOD) ve katalaz (CAT) düzeyleri oksidatif stres belirteçleri olarak; tümör nekroz faktör-alfa (TNF-α) ve interlökin-1 beta (IL-1β) düzeyleri ise inflamatuar parametreler olarak değerlendirildi. Ayrıca histopatolojik değişiklikler ile indüklenebilir nitrik oksit sentaz (iNOS) ve alfa-düz kas aktini (α-SMA) immünoreaktivitesi incelendi. Bulgular: AlCl₃ uygulaması kalp dokusunda MDA düzeylerini artırırken, GSH düzeyleri ile SOD ve CAT aktivitelerini azalttı (P<0.01). ESC tedavisi her iki doz grubunda bu değişiklikleri anlamlı düzeyde tersine çevirdi (P<0.01). Ayrıca, ESC uygulanan gruplarda TNF-α ve IL-1β düzeyleri AlCl₃ grubuna kıyasla daha düşük bulundu (P<0.01). Histopatolojik incelemede ESC gruplarında miyokardiyal hasarın azaldığı gözlenirken, immünohistokimyasal analizde iNOS ve α-SMA immünoreaktivitesinde azalma saptandı. Koruyucu etkilerin 100 mg/kg ESC uygulanan grupta daha belirgin olduğu dikkati çekti. Sonuç: ESC, oksidatif stres ve inflamatuvar yanıtları modüle ederek, histopatolojik bulguları iyileştirerek ve profibrotik değişiklikler üzerinde etkili olarak AlCl₃ kaynaklı kardiyotoksisiteyi hafifletmektedir. Her iki ESC dozu da koruyucu etkiler göstermiş olup, yüksek doz grubunda genel olarak daha fazla iyileşme saptanmıştır.

Anahtar Kelimeler

• Alüminyum klorür
• esculetin
• inflamasyon
• kardiyotoksisite
• oksidatif stres

Kaynakça

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