Doksorubisin ile oluşturulmuş kalp iskemi modelinde vinpocetinin koruyucu ve tedavi edici etkisinin araştırılması
Küçük Resim Yok
Tarih
2018
Yazarlar
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
İnönü Üniversitesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Amaç: Doksorubisin yaygın olarak kullanılan antrasiklin türevi bir antineoplastik ajandır. Bununla birlikte başta kardiyotoksisite olmak üzere ortaya çıkan ciddi yan etkiler doksorubisinin kullanımını kısıtlamaktadır. Bu durum hem doksorubisinin neden olduğu kardiyotoksisitenin mekanizmasının anlaşılması, hem de önlenmesi ve tedavi edilmesi ile ilgili çalışmalar yapılmasını zorunlu kılmaktadır. Bu çalışmada ratlarda doksorubisin ile deneysel olarak oluşturulan kardiyotoksisite üzerine güçlü bir antioksidan ve antienflamatuar olan vinposetinin koruyucu ve tedavi edici etkisini araştırmak amaçlanmıştır. Gereç ve Yöntemler: Bu çalışmada ağırlıkları tahmini olarak 250-500 gram olan Wistar albino ırkı 32 adet erkek rat kullanılmıştır. Ratlar her biri 8 adetten oluşan 4 gruba ayrılmıştır. Grup 1 (KONTROL grubu)'e herhangi bir ilaç uygulanmadı. Grup 2 (DOX grubu)' ye çalışmanın birinci gününde 20 mg/kg dozunda doksorubisin i.p. olarak tek doz uygulandı ve 2 gün sonra deney yapıldı. Grup 3 (VİNPO grubu)'e 3 gün boyunca 10 mg/kg dozunda vinpocetin i.p. uygulandı. Grup 4 (Mİ öncesi VİNPO -VİNPO + DOX- grubu)'e 30 dakika önce 10 mg/kg VİNPO uygulandıktan sonra 20 mg/kg DOX tek doz ve daha sonraki 2 gün daha 10 mg/kg VİNPO uygulandı. Doksorubisin uygulanmasının 48. saatinde anestezi altındaki ratlara karotis arter kanülasyonu yapılarak ve göğüs EKG elektrotları bağlanmak sureti ile EKG, kalp hızı, kan basıncı ve oksijen satürasyonu ölçüldü. Kayıt alma işlemleri sona erince kalp ve damar doku örnekleri alınarak histopatolojik ve biyokimysal incelemeler yapıldı. Alınan kan örneklerinden troponin-I, Kreatin kinaz (CK) ve Kreatin kinaz kardiyak izoenzim (kütle CK-MB) düzeyleri ölçüldü. Kalp ve damar dokusunda antioksidan sistem ve oksidatif stres markerları olarak; Malonildialdehit (MDA), Superoksitdismutaz (SOD), Katalaz (CAT) ve redükte glutatyon (GSH) tayini yapıldı. Ayrıca histolojik değerlendirmeler için hematoksilen-eozin (H-E) ve kaspaz-3 immün boyama metodu uygulandı. Bulgular:Yapılan çalışmada DOX tedavisinin istatistiksel olarak anlamlı bir fark yaratmasa da ratlarda troponin-I düzeyinde yükselmeye neden olduğu, VİNPO+DOX grubunda ise bu yükselmenin olmadığı görüldü. Ayrıca DOX grubunda kalp hızı, sistolik kan basıncı, diastolik kan basıncı ve ortalama kan basıncı değerlerinin kontrol grubuna göre daha yüksek olduğu, VİNPO+DOX grubunda da bu değşikliklerin benzer şekilde devam ettiği görüldü. Gruplar arasında T negatifliği haricinde EKG bulguları açısından herhangi bir fark izlenmedi. DOX grubundaki T negatifliklerinin VİNPO+DOX grubunda da devam ettiği görüldü. Miyokardiyal katalaz aktivitesinin DOX ve VİNPO+DOX gruplarında anlamlı bir şekilde diğer gruplardan yüksek olduğu (p<0.05), istatistiksel olarak anlam ifade etmese de DOX grubunda MDA aktivitesinin arttığı, VİNPO+DOX grubunda ise kontrol grubuna yakın düzeyde ölçüldüğü gözlendi. Damar dokusunda ise DOX uygulanması cat ve SOD düzeylerinin anlamlı düşüşüne yol açmış, VİNPO+DOX grubunda ise bu değerler kontrol grubuna yakın seviyelerde ölçülmüştür (p<0.05). Histopatolojik incelemelerde kalp dokusunda DOX grubunda görülen bulgular kontrol grubundan anlamlı bir şekilde farklılık göstermekteyken (p<0.05), VİNPO+DOX grubunda DOX grubundaki değişikliklerin benzer şekilde devam ettiği görüldü (p>0.05). Damar dokusunda histopatolojik incelemelerde gruplar arasında anlamlı bir fark izlenmedi (p<0.05). Hem kardiyomiyositlerin sitoplazmasında hem de vasküler düz kas hücrelerinde izlenen kaspaz-3 immünreaktivitesinin istatistiksel olarak anlamlı bir fark olmasa da (p>0.05) DOX grubunda daha yüksek olduğu görüldü. Bununla birlikte VİNPO+DOX grubunda kaspaz-3 immünreaktivitesi açısından DOX grubundan farklı değildi. Sonuç: Bu çalışma doksorubisin ile oluşturulan kardiyotoksisite üzerine vinposetinin koruyucu ve tedavi edici etkilerinin araştırıldığı ilk çalışmadır. Biyokimyasal testler ve bazı doku belirteçleri anlamında vinposetinin doksorubisinin neden olduğu değişiklikleri kısmen geriye döndürdüğü izlenmiştir. Fakat bu etki hemodinamik parametreler, EKG bulguları ve histopatolojik olarak desteklenmemiştir.Antiinflamatuvar, antioksidan, nöroprotektif etkileri olduğu bilinen vinposetin ile ilgili daha fazla sayıda rat ile ve daha uzun süreli yapılacak çalışmalar kardiyoprotektif etkilerinin belirlenmesi, ortaya konması adına yararlı olacaktır. Anahtar kelimeler: Doksorubisin, vinposetin, doksorubisin kardiyotoksisitesi
Objective: Doxorubicin is a widely used anthracycline derivative antineoplastic agent. However, serious side effects, especially cardiotoxicity, limit the use of doxorubicin. This situation necessitates both the understanding of the mechanism of cardiotoxicity caused by doxorubicin, as well as the studies related to the prevention and treatment of it. In this study, we aimed to investigate the protective and therapeutic effect of vinposetin, a potent antioxidant and antiinflammatory agent, on cardiotoxicity experimentally induced by doxorubicin in rats. Material and Methods: In this study, 32 male Wistar albino rats weighing approximately 250-500 grams were used. The rats are divided into 4 groups of 8 each. Group 1 (CONTROL group) did not receive any medication. On the first day of study in group 2 (DOX group), a single dose of doxorubicin 20 mg / kg was administered intraperitoneally and the test was performed after 2 days. Group 3 (VINPO group) received vinpocetine at a dose of 10 mg / kg intraperitoneally for 3 days. Group 4 (VINPO before MI-VINPO+DOX group) was administered 10 mg / kg VINPO 30 minutes before, and then 20 mg / kg DOX single dose and then another 10 mg / kg VINPO for 2 days thereafter. At 48 hours of doxorubicin administration, ECG, heart rate, blood pressure and oxygen saturation were measured by carotid artery cannulation under anesthesia and by attaching chest ECG electrodes. At the end of the registration procedure, heart and vessel tissue specimens were taken and histopathological and biochemical examinations were performed. Troponin-I, creatine kinase (CK), and creatine kinase cardiac isoenzyme (mass CK-MB) levels were measured in the blood samples. Malonyldialdehyde (MDA), Superoxide dismutase (SOD), Catalase (CAT) and Reduced Glutathione (GSH) were assayed as antioxidant system and oxidative stress markers in heart and vessel tissue. Hematoxylin-eosin (H-E) and caspase-3 immunostaining were also applied for histological evaluations. Findings: Although there was no statistically significant difference, it was seen that DOX administration increased the troponin-I level in rats, whereas it was not observed in the VİNPO + DOX group. In the DOX group, heart rate, systolic blood pressure, diastolic blood pressure and mean blood pressure values were found to be higher than the control group, and it was seen that these changes were similar in the VINPO + DOX group. There was no difference between the groups in terms of ECG findings except T negative. The T negatives in the DOX group were also observed in the VINPO + DOX group. It was observed that myocardial catalase activity was significantly higher in the DOX and VINPO + DOX groups than in the other groups (p <0.05). Although not statistically significant, it was observed that the MDA activity was increased in the DOX group and, it was measured close to the control group in the VINPO + DOX group. In vessel tissue, administration of DOX resulted in a significant decrease in cat and SOD levels and in the VINPO + DOX group, these values were measured at levels close to the control group (p <0.05). Histopathological findings showed that the heart tissue was significantly different from the control group (p <0.05) in the DOX group, while the changes in the DOX group and in the VINPO + DOX group were similar (p> 0.05). There was no significant difference between the groups in histopathological examinations (p <0.05). The caspase-3 immunoreactivity observed both in the cytoplasm of cardiomyocytes and in vascular smooth muscle cells was found to be higher in the DOX group, although not statistically significant (p> 0.05). However, the caspase-3 immunoreactivity in the VINPO + DOX group was not different from the DOX group. Conclusion:This is the first study to investigate the protective and therapeutic effects of vinposetine on doxorubicin-induced cardiotoxicity. It has been observed that vinpocetine partially reverses the changes caused by doxorubicin at the level of biochemical tests and some tissue markers. However, this effect was not supported by haemodynamic parameters, ECG findings and histopathologically. Studies with more rats and longer-term will be helpful in determining cardioprotective effects of vinpocetine, known to have antiinflammatory, antioxidant and neuroprotective effects. Key words: doxorubicin, vinpocetine, doxorubicin cardiotoxicity.
Objective: Doxorubicin is a widely used anthracycline derivative antineoplastic agent. However, serious side effects, especially cardiotoxicity, limit the use of doxorubicin. This situation necessitates both the understanding of the mechanism of cardiotoxicity caused by doxorubicin, as well as the studies related to the prevention and treatment of it. In this study, we aimed to investigate the protective and therapeutic effect of vinposetin, a potent antioxidant and antiinflammatory agent, on cardiotoxicity experimentally induced by doxorubicin in rats. Material and Methods: In this study, 32 male Wistar albino rats weighing approximately 250-500 grams were used. The rats are divided into 4 groups of 8 each. Group 1 (CONTROL group) did not receive any medication. On the first day of study in group 2 (DOX group), a single dose of doxorubicin 20 mg / kg was administered intraperitoneally and the test was performed after 2 days. Group 3 (VINPO group) received vinpocetine at a dose of 10 mg / kg intraperitoneally for 3 days. Group 4 (VINPO before MI-VINPO+DOX group) was administered 10 mg / kg VINPO 30 minutes before, and then 20 mg / kg DOX single dose and then another 10 mg / kg VINPO for 2 days thereafter. At 48 hours of doxorubicin administration, ECG, heart rate, blood pressure and oxygen saturation were measured by carotid artery cannulation under anesthesia and by attaching chest ECG electrodes. At the end of the registration procedure, heart and vessel tissue specimens were taken and histopathological and biochemical examinations were performed. Troponin-I, creatine kinase (CK), and creatine kinase cardiac isoenzyme (mass CK-MB) levels were measured in the blood samples. Malonyldialdehyde (MDA), Superoxide dismutase (SOD), Catalase (CAT) and Reduced Glutathione (GSH) were assayed as antioxidant system and oxidative stress markers in heart and vessel tissue. Hematoxylin-eosin (H-E) and caspase-3 immunostaining were also applied for histological evaluations. Findings: Although there was no statistically significant difference, it was seen that DOX administration increased the troponin-I level in rats, whereas it was not observed in the VİNPO + DOX group. In the DOX group, heart rate, systolic blood pressure, diastolic blood pressure and mean blood pressure values were found to be higher than the control group, and it was seen that these changes were similar in the VINPO + DOX group. There was no difference between the groups in terms of ECG findings except T negative. The T negatives in the DOX group were also observed in the VINPO + DOX group. It was observed that myocardial catalase activity was significantly higher in the DOX and VINPO + DOX groups than in the other groups (p <0.05). Although not statistically significant, it was observed that the MDA activity was increased in the DOX group and, it was measured close to the control group in the VINPO + DOX group. In vessel tissue, administration of DOX resulted in a significant decrease in cat and SOD levels and in the VINPO + DOX group, these values were measured at levels close to the control group (p <0.05). Histopathological findings showed that the heart tissue was significantly different from the control group (p <0.05) in the DOX group, while the changes in the DOX group and in the VINPO + DOX group were similar (p> 0.05). There was no significant difference between the groups in histopathological examinations (p <0.05). The caspase-3 immunoreactivity observed both in the cytoplasm of cardiomyocytes and in vascular smooth muscle cells was found to be higher in the DOX group, although not statistically significant (p> 0.05). However, the caspase-3 immunoreactivity in the VINPO + DOX group was not different from the DOX group. Conclusion:This is the first study to investigate the protective and therapeutic effects of vinposetine on doxorubicin-induced cardiotoxicity. It has been observed that vinpocetine partially reverses the changes caused by doxorubicin at the level of biochemical tests and some tissue markers. However, this effect was not supported by haemodynamic parameters, ECG findings and histopathologically. Studies with more rats and longer-term will be helpful in determining cardioprotective effects of vinpocetine, known to have antiinflammatory, antioxidant and neuroprotective effects. Key words: doxorubicin, vinpocetine, doxorubicin cardiotoxicity.
Açıklama
Anahtar Kelimeler
İlk ve Acil Yardım, Emergency and First Aid
