Publication: Trinitrobenzen sulfonik asit ile oluşturulan kolit modelinde kronik St. John’s Wort uygulamasının tedavi edici etkisinin spironolakton ile karşılaştırmalı olarak incelenmesi
Abstract
1.ÖZET Bu çalışmanın amacı trinitrobenzen sülfonik asit (TNBS) ile kolit oluşturulmuş sıçanların ileum, jejenum ve kolon mukozalarında oluşan inflamasyon ve immün yanıtlar üzerine Hypericum perforatum (HP)’dan hazırlanan bir preparat olan St. John’s wort’ün (SJW) tedavi edici bir etkisinin olup olmadığını, spironolakton (SPL) ile karşılaştırmalı olarak incelemektir. İnflamasyon ile nükleer bir reseptör olan Pregnan X Reseptör (PXR) arasında ters bir ilişki olduğu bilinmektedir. P-glikoproteinler (P-gp) ise efflux proteinleridir ve inflamatuvar barsak hastalıklarında (İBH) P-gp ekspresyonunun bozulduğu bildirilmiştir. Spironolakton ve SJW, her ikisi de güçlü enzim indüksiyonu yapan, bu arada PXR ve P-gpleri de indükleyen bileşiklerdir, dolayısı ile dokuda inflamasyonu baskılamaları beklenir. Çalışmada Wistar Albino sıçanlar kullanılmış, denekler kontrol ve kolit olmak üzere 2 ana gruba ayrılmıştır. Her iki grup da kendi aralarında 3’er alt-gruba ayrılmış, birinci alt-gruplara serum fizyolojik (SF), ikinci alt-gruplara SJW (300 mg/ kg günde 2 kez), ücüncü alt-gruplara ise SPL (200µmol/ kg günde 2 kez) 7 gün süre ile uygulanmıştır. Çalışmanın sonunda hayvanlar sakrifiye edilerek kan ve doku örnekleri alınmış, makroskobik skorlama yapılmış, serumda nukleer faktör kappa B (NF-κB ) ve Tümör Nekroz Faktör-α (TNF-α) seviyeleri; dokularda ise MPO aktivitesi, serbest oksijen radikali seviyeleri ölçülmüştür. Her iki ilaçla tedavinin de kolite bağlı doku hasarını azalttığı, kolit grubunda yükselmiş olan serum TNF-α ve NF-κB düzeylerinin ve dokuda nötrofil infiltrasyonunun bir göstergesi olan MPO aktivitesinin tedavi edilen kolit gruplarında daha düşük olduğu gözlenmiştir. Kolit grubunda azalmış görünen PXR ve P-gp ekspresyonunun da tedavi gruplarında eski seviyelere yükselmiştir. Sonuç olarak, hem SPL hem de SJW’nin muhtemelen PXR ve P-gp indüksiyonu yaparak, ayrıca olası antioksidan etkileri ile de inflamasyonu önledikleri sonucuna varılmıştır. SJW’nin antidepresan özelliği nedeni ile de İBH tedavisinde yararlı olabileceği düşünülmektedir. Anahtar Sözcükler: St. John’s Wort, Spironolakton, İBH, PXR, P-gp 1.
Effect of Treatment with St.John’s Wort or Spironolactone on Trinitrobenzini Sulphonic Acid induced Colitis of The Rats The aim of this study was to investigate and compare the effects of treatment with St.John’s Wort (SJW) or spironolactone (SPL) on TNBS induced colitis of the rats. Both SJW and SPL have strong enzyme inducing properties, and they also induce the Pregnane X receptor (PXR) and the efflux protein P-glycoprotein(P-gp). The nuclear receptor PXR regulates many genes that are important for drug metabolism and drug distribution. A mutual repression between PXR and inflammation has also been demonstrated. P-gp is an efflux protein and it has been reported that the P-gp expression is deficient in people with IBD. This study was conducted on Wistar Albino (250-300 g) rats. The subjects were divided into the control and TNBS colitis groups. Each group was again divided into three subgroups. First subgroup (control) received normal saline, the second subgroup received SJW(300 mg/ kg twice a day) and the third subgroup received SPL(200 µmol/ kg twice a day) orally for 7days. At the end of the study, 18 hours after the last dose of the drug, after sacrificing the animals, blood and tissue samples were collected for various studies. Intestinal tissues were evaluated macroscopically according to Millar. Macroscopic scores that were increased during colitis were decreased significantly after both treatments. The serum levels of NF-ĸB, TNF- and the tissue MPO activity as well as the oxidant damage that were increased during colitis were decreased significantly after both SJW and SPL treatments. PXR and P-gp expression of the tissues (which were evaluated by immunohistochemistry) in the SJW and SPL treated groups were almost the same as the control groups. In conclusion, it was observed that both SPL and SJW had beneficial effects in the treatment of TNBS colitis of the rats, most probably due to their PXR and P-gp inducing properties. SJW might prove to be beneficial in the treatment of human IBDs also via its antidepressant properties. Key Words: St. John’s Wort, Spironolactone, IBD, PXR, P-gp
Effect of Treatment with St.John’s Wort or Spironolactone on Trinitrobenzini Sulphonic Acid induced Colitis of The Rats The aim of this study was to investigate and compare the effects of treatment with St.John’s Wort (SJW) or spironolactone (SPL) on TNBS induced colitis of the rats. Both SJW and SPL have strong enzyme inducing properties, and they also induce the Pregnane X receptor (PXR) and the efflux protein P-glycoprotein(P-gp). The nuclear receptor PXR regulates many genes that are important for drug metabolism and drug distribution. A mutual repression between PXR and inflammation has also been demonstrated. P-gp is an efflux protein and it has been reported that the P-gp expression is deficient in people with IBD. This study was conducted on Wistar Albino (250-300 g) rats. The subjects were divided into the control and TNBS colitis groups. Each group was again divided into three subgroups. First subgroup (control) received normal saline, the second subgroup received SJW(300 mg/ kg twice a day) and the third subgroup received SPL(200 µmol/ kg twice a day) orally for 7days. At the end of the study, 18 hours after the last dose of the drug, after sacrificing the animals, blood and tissue samples were collected for various studies. Intestinal tissues were evaluated macroscopically according to Millar. Macroscopic scores that were increased during colitis were decreased significantly after both treatments. The serum levels of NF-ĸB, TNF- and the tissue MPO activity as well as the oxidant damage that were increased during colitis were decreased significantly after both SJW and SPL treatments. PXR and P-gp expression of the tissues (which were evaluated by immunohistochemistry) in the SJW and SPL treated groups were almost the same as the control groups. In conclusion, it was observed that both SPL and SJW had beneficial effects in the treatment of TNBS colitis of the rats, most probably due to their PXR and P-gp inducing properties. SJW might prove to be beneficial in the treatment of human IBDs also via its antidepressant properties. Key Words: St. John’s Wort, Spironolactone, IBD, PXR, P-gp