Glucagon-like peptide-2 May Assist to Protect against Valproic Acid Induced Hepatic Injury in Rats

Abstract

VPA is widely used in epilepsy and other psychological disorders, increasing the probability of developing non-alcoholic liver disease in long-term treatments. GLP-2 is a proglucagon belonging to the peptide family expressed in the intestine, pancreas and brain to date. Although there are many studies on the use of GLP-2 for therapeutic purposes on the gastrointestinal system, its effect on liver toxicity is unknown. We aimed to investigate the effect of GLP-2 administration on hepatic function in a rat model with VPA-induced hepatotoxicity. Rats were injected intraperitoneally at 500 mg/kg and GLP-2 5µg/kg a day. The rats (200-250g) were separated into four groups (n=7). Group C was administrated 1 mL of 0.9% SF, Group GLP treated with GLP-2 (5µg/kg/day), Group GLP+VPA were received GLP-2 (5µg/kg) 1 h prior to VPA (500 mg/kg), Group VPA received VPA (500 mg/kg), 1 h prior to 1 mL of 0.9% SF ip (n=7). Liver tissues were used to investigate effects of VPA and GLP-2 in the liver 15 days after application. While VPA caused moderate but significant liver damage according to biochemical results, mRNA expression of cytokines were found to significantly increase after the day 15. VPA administration significantly induced expression of Interleukin 1 beta (IL-1β), Tumor necrosis factor alpha (TNF-α), Interleukin 10 (IL-10). In contrast, GLP-2 treatment reduced expression of IL-1β, TNF-α and IL-10. Also malondialdehyde (MDA), glutathione s-transferase (α-GST), superoxide dismutase activities (SOD), total antioxidant status (TAS) and total oxidant status (TOS) levels were estimated. GLP-2 had positive effects on both liver enzymes and oxidative stress markers in VPA-induced hepatotoxicity. These results suggest that endogenous GLP-2 administration is associated with a mechanism that moderately protects liver tissue.  

Keywords

• Glucagon-like peptide-2 (GLP-2),Valproic acid (VPA),Hepatoprotective effect

Glukagon benzeri peptit-2 Sıçanlarda Valproik Asite Bağlı Hepatik Yaralanmaya Karşı Korunmaya Yardımcı Olabilir

Öz

Valproik asit (VPA), epilepsi ve diğer psikolojik bozuklukların uzun süreli tedavilerinde yaygın olarak kullanılmakta, alkolik olmayan yağlı karaciğer hastalığı gelişme riskini artırmaktadır. Bugüne kadar, GLP-2, bağırsak, pankreas ve beyinde eksprese edilen peptit familyasına ait bir proglukagondur. GLP-2'nin gastrointestinal sistem üzerinde tedavi amaçlı kullanımına dair birçok çalışma olmasına rağmen, karaciğer toksisitesine olan etkisi bilinmemektedir. Bu çalışmada VPA ile hepatotoksisite oluşturulmuş sıçan modelinde GLP-2 uygulamasının hepatik fonksiyon üzerindeki etkisini araştırmayı amaçladık. Sıçanlara intraperitonal olarak 500 mg/kg/gün ve GLP-2 (5 µg /kg/gün) enjekte edildi. Sıçanlar (200-250g) dört gruba ayrıldı (n=7). C grubuna 1 mL % 0.9 tuzlu su verildi, GLP-2 grubuna 5 µg /kg/gün GLP-2 verildi, Grup GLP+VPA’ya, VPA'dan (500 mg/kg) 1 saat önce GLP-2 (5 µg/kg) verildi. Grup VPA, 1 mL %0.9 tuzlu sudan 1 saat önce VPA (500 mg/kg) aldı. Uygulamadan 15 gün sonra karaciğerdeki VPA ve GLP-2 etkilerini araştırmak için karaciğer dokuları kullanıldı. VPA, biyokimyasal sonuçlara göre orta fakat önemli karaciğer hasarına neden olurken, sitokinlerin mRNA ekspresyonunun kontrol grubuna göre 15. günden sonra önemli ölçüde arttığı bulunmuştur. VPA uygulaması Interleukin 1 beta (IL-1β), Tümör nekroz faktörü alfa (TNF-α), İnterlökin 10 (IL-10) ekspresyonunu artırırken, aksine, GLP-2, IL-l β, TNF-α ve IL-10 ekspresyonunu azaltmıştır. Ayrıca malondialdehit (MDA), glutatyon s-transferaz (α-GST), süperoksit dismutaz aktiviteleri (SOD), toplam antioksidan status (TAS) ve toplam oksidan status (TOS) seviyeleri ölçüldü. GLP-2'nin VPA kaynaklı hepatotoksisitede hem karaciğer enzimleri hem de oksidatif stres belirteçleri üzerinde olumlu etkileri olmuştur. Bu sonuçlar endojen GLP-2 uygulamasının, karaciğer dokusunu orta derecede koruyan bir mekanizma ile ilişkili olduğunu düşündürmektedir.

Anahtar Kelimeler

• Glukagon benzeri peptit-2 (GLP-2),Valproik asit (VPA),Hepatoprotektif etki

Kaynakça

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