Research Article
BibTex RIS Cite

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

Year 2020, Issue: 19, 297 - 302, 31.08.2020
https://doi.org/10.31590/ejosat.711063

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.  

References

  • Ahangar, N., Naderi, M., Noroozi, A., Ghasemi, M., Zamani, E., & Shaki, F. (2017). Zinc deficiency and oxidative stress involved in valproic acid induced hepatotoxicity: protection by zinc and selenium supplementation. Biological trace element research, 179(1), 102-109.
  • Akşit, H., Akşit, D., Bildik, A., Hatibe, K. A. R. A., Yavuz, Ö., & Seyrek, K. (2015). Deneysel karaciğer intoksikasyonunda N-asetil sistein’in glutatyon metabolizması ve lipid peroksidasyonuna etkileri. Ankara Üniversitesi Veteriner Fakültesi Dergisi, 62(1), 1-5.
  • Alavi, K., Schwartz, M. Z., Palazzo, J. P., & Prasad, R. (2000). Treatment of inflammatory bowel disease in a rodent model with the intestinal growth factor glucagon-like peptide-2. Journal of pediatric surgery, 35(6), 847-851.
  • Arda-Pirincci, P., & Bolkent, S. (2011). The role of glucagon-like peptide-2 on apoptosis, cell proliferation, and oxidant– antioxidant system at a mouse model of intestinal injury induced by tumor necrosis factor-alpha/actinomycin D. Molecular and cellular biochemistry, 350(1-2), 13-27.
  • Bambini-Junior, V., Rodrigues, L., Behr, G. A., Moreira, J. C. F., Riesgo, R., & Gottfried, C. (2011). Animal model of autism induced by prenatal exposure to valproate: behavioral changes and liver parameters. Brain research, 1408, 8-16.
  • Boushey, R. P., Yusta, B., & Drucker, D. J. (1999). Glucagon-like peptide 2 decreases mortality and reduces the severity of indomethacin-induced murine enteritis. American Journal of Physiology-Endocrinology And Metabolism, 277(5), E937-E947.
  • Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O (2012). Oxidative stress and antioxidant defense. World Allergy Organ J 5:9–19
  • Chen, G. W., Chen, T. Y., & Yang, P. M. (2019). Differential effect of herbal tea extracts on free fatty acids-ethanol-and acetaminophen-induced hepatotoxicity in FL83B hepatocytes. Drug and chemical toxicology, 1-6.
  • Chen, Y., Zhou, J., Xu, S., Liu, M., Wang, M., Ma, Y., Zhao, M., Wang, Z., Guo, Y. & Zhao, L. (2019). Association between the perturbation of bile acid homeostasis and valproic acid-induced hepatotoxicity. Biochemical Pharmacology, 170, 113669.
  • Clarke, H., Egan, D. A., Heffernan, M., Doyle, S., Byrne, C., Kilty, C., and Ryan, M. P. (1997). Alpha-glutathione S-transferase (alpha-GST) release, an early indicator of carbon tetrachloride hepatotoxicity in the rat. Hum. Exp. Toxicol. 16 , 154–157.
  • Diederich, M., Chateauvieux, S., Morceau, F., & Dicato, M. (2010). Molecular and therapeutic potential and toxicity of valproic acid. J Biomed Biotechnol, 2010, 201.
  • Drucker, D. J. (2002). Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology, 122(2), 531-544.
  • Drucker, D. J., Yusta, B., Boushey, R. P., DeForest, L., & Brubaker, P. L. (1999). Human [Gly2] GLP-2 reduces the severity of colonic injury in a murine model of experimental colitis. American Journal of Physiology-Gastrointestinal and Liver Physiology, 276(1), G79-G91.
  • Fourcade,S., Ruiz, M., Guilera, C., Hahnen E, Brichta L, Naudi A, Portero-Otín M, Dacremont G, Cartier N, Wanders R, Kemp S, Mandel JL, Wirth B, Pamplona R, Aubourg P, Pujol A (2010). Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy. Hum Mol Genet 19:2005–2014 .
  • Ghodke-Puranik, Y., Thorn, C. F., Lamba, J. K., Leeder, J. S., Song, W., Birnbaum, A. K, Altman R.B & Klein, T. E. (2013). Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenetics and genomics, 23(4), 236.
  • Guan, X., Stoll, B., Lu, X., Tappenden, K. A., Holst, J. J., Hartmann, B., & Burrin, D. G. (2003). GLP-2-mediated up-regulation of intestinal blood flow and glucose uptake is nitric oxide-dependent in TPN-fed piglets. Gastroenterology, 125(1), 136-147.
  • Guo, H. L., Jing, X., Sun, J. Y., Hu, Y. H., Xu, Z. J., Ni, M. M., ..& Wang, T. (2019). Valproic Acid and the Liver Injury in Patients with Epilepsy: An Update. Current pharmaceutical design, 25(3), 343-351.
  • Hartmann, B., Johnsen, A. H., Ørskov, C., Adelhorst, K., Thim, L., & Holst, J. J. (2000). Structure, measurement, and secretion of human glucagon-like peptide-2. Peptides, 21(1), 73-80.
  • Jin, J., Xiong, T., Hou, X., Sun, X., Liao, J., Huang, Z., ..& Zhao, Z. (2014). Role of Nrf2 activation and NF-κB inhibition in valproic acid induced hepatotoxicity and in diammonium glycyrrhizinate induced protection in mice. Food and chemical toxicology, 73, 95-104.
  • Karaca, Ö., Sunay, F. B., Kuş, M. A., Gülcen, B., Özcan, E., Ögetürk, M., & Kuş, İ. (2014). Kadmiyum ile Oluşturulan Deneysel Karaciğer Hasarına Karşı Melatoninin Etkilerinin Biyokimyasal ve Histopatolojik Düzeylerde İncelenmesi. Fırat Tıp Derg, 19(3), 110- 115
  • Kiang,TK., Teng, XW, Karagiozov S, Surendradoss J, Chang TK, Abbott FS (2010). Role of oxidative metabolism in the effect of valproic acid on markers of cell viability, necrosis, and oxidative stress in sandwich-cultured rat hepatocytes. Toxicol Sci 118:501–509
  • Lim, D. W., Wales, P. W., Josephson, J. K., Nation, P. N., Wizzard, P. R., Sergi, C. M., .. & Turner, J. M. (2016). GlucagonLike Peptide 2 Improves Cholestasis in Parenteral Nutrition–Associated Liver Disease. Journal of Parenteral and Enteral Nutrition, 40(1), 14-21.
  • Mercan, U. (2004). Toksikolojide serbest radikallerin önemi. Yüzüncü Yıl Üniversitesi Veteriner Fakültesi Dergisi, 15(1), 9196.
  • Munroe, D. G., Gupta, A. K., Kooshesh, F., Vyas, T. B., Rizkalla, G., Wang, H., ... & McCallum, K. (1999). Prototypic G protein-coupled receptor for the intestinotrophic factor glucagon-like peptide 2. Proceedings of the National Academy of Sciences, 96(4), 1569-1573.
  • Neuman, M. G. (2019). Biomarkers of drug-induced liver toxicity. Therapeutic drug monitoring, 41(2), 227-234.
  • Springer, C., & Nappe, T. M. (2019). Anticonvulsants Toxicity. In StatPearls [Internet]. StatPearls Publishing.
  • Tong, V., Teng, X. W., Chang, T. K., & Abbott, F. S. (2005). Valproic acid I: time course of lipid peroxidation biomarkers, liver toxicity, and valproic acid metabolite levels in rats. Toxicological Sciences, 86(2), 427-435.
  • Tong, V., Teng XW, Chang TK, Abbott FS (2005b).Valproic acid I: time course of lipid peroxidation biomarkers, liver toxicity, and valproic acid metabolite levels in rats. Toxicol Sci 86:427–435
  • Zhang, W., Zhu, W., Zhang, J., Li, N., & Li, J. (2008). Protective effects of glucagon‐like peptide 2 on intestinal ischemia reperfusion rats. Microsurgery: Official Journal of the International Microsurgical Society and the European Federation of Societies for Microsurgery, 28(4), 285-290.

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

Year 2020, Issue: 19, 297 - 302, 31.08.2020
https://doi.org/10.31590/ejosat.711063

Abstract

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.

References

  • Ahangar, N., Naderi, M., Noroozi, A., Ghasemi, M., Zamani, E., & Shaki, F. (2017). Zinc deficiency and oxidative stress involved in valproic acid induced hepatotoxicity: protection by zinc and selenium supplementation. Biological trace element research, 179(1), 102-109.
  • Akşit, H., Akşit, D., Bildik, A., Hatibe, K. A. R. A., Yavuz, Ö., & Seyrek, K. (2015). Deneysel karaciğer intoksikasyonunda N-asetil sistein’in glutatyon metabolizması ve lipid peroksidasyonuna etkileri. Ankara Üniversitesi Veteriner Fakültesi Dergisi, 62(1), 1-5.
  • Alavi, K., Schwartz, M. Z., Palazzo, J. P., & Prasad, R. (2000). Treatment of inflammatory bowel disease in a rodent model with the intestinal growth factor glucagon-like peptide-2. Journal of pediatric surgery, 35(6), 847-851.
  • Arda-Pirincci, P., & Bolkent, S. (2011). The role of glucagon-like peptide-2 on apoptosis, cell proliferation, and oxidant– antioxidant system at a mouse model of intestinal injury induced by tumor necrosis factor-alpha/actinomycin D. Molecular and cellular biochemistry, 350(1-2), 13-27.
  • Bambini-Junior, V., Rodrigues, L., Behr, G. A., Moreira, J. C. F., Riesgo, R., & Gottfried, C. (2011). Animal model of autism induced by prenatal exposure to valproate: behavioral changes and liver parameters. Brain research, 1408, 8-16.
  • Boushey, R. P., Yusta, B., & Drucker, D. J. (1999). Glucagon-like peptide 2 decreases mortality and reduces the severity of indomethacin-induced murine enteritis. American Journal of Physiology-Endocrinology And Metabolism, 277(5), E937-E947.
  • Birben E, Sahiner UM, Sackesen C, Erzurum S, Kalayci O (2012). Oxidative stress and antioxidant defense. World Allergy Organ J 5:9–19
  • Chen, G. W., Chen, T. Y., & Yang, P. M. (2019). Differential effect of herbal tea extracts on free fatty acids-ethanol-and acetaminophen-induced hepatotoxicity in FL83B hepatocytes. Drug and chemical toxicology, 1-6.
  • Chen, Y., Zhou, J., Xu, S., Liu, M., Wang, M., Ma, Y., Zhao, M., Wang, Z., Guo, Y. & Zhao, L. (2019). Association between the perturbation of bile acid homeostasis and valproic acid-induced hepatotoxicity. Biochemical Pharmacology, 170, 113669.
  • Clarke, H., Egan, D. A., Heffernan, M., Doyle, S., Byrne, C., Kilty, C., and Ryan, M. P. (1997). Alpha-glutathione S-transferase (alpha-GST) release, an early indicator of carbon tetrachloride hepatotoxicity in the rat. Hum. Exp. Toxicol. 16 , 154–157.
  • Diederich, M., Chateauvieux, S., Morceau, F., & Dicato, M. (2010). Molecular and therapeutic potential and toxicity of valproic acid. J Biomed Biotechnol, 2010, 201.
  • Drucker, D. J. (2002). Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology, 122(2), 531-544.
  • Drucker, D. J., Yusta, B., Boushey, R. P., DeForest, L., & Brubaker, P. L. (1999). Human [Gly2] GLP-2 reduces the severity of colonic injury in a murine model of experimental colitis. American Journal of Physiology-Gastrointestinal and Liver Physiology, 276(1), G79-G91.
  • Fourcade,S., Ruiz, M., Guilera, C., Hahnen E, Brichta L, Naudi A, Portero-Otín M, Dacremont G, Cartier N, Wanders R, Kemp S, Mandel JL, Wirth B, Pamplona R, Aubourg P, Pujol A (2010). Valproic acid induces antioxidant effects in X-linked adrenoleukodystrophy. Hum Mol Genet 19:2005–2014 .
  • Ghodke-Puranik, Y., Thorn, C. F., Lamba, J. K., Leeder, J. S., Song, W., Birnbaum, A. K, Altman R.B & Klein, T. E. (2013). Valproic acid pathway: pharmacokinetics and pharmacodynamics. Pharmacogenetics and genomics, 23(4), 236.
  • Guan, X., Stoll, B., Lu, X., Tappenden, K. A., Holst, J. J., Hartmann, B., & Burrin, D. G. (2003). GLP-2-mediated up-regulation of intestinal blood flow and glucose uptake is nitric oxide-dependent in TPN-fed piglets. Gastroenterology, 125(1), 136-147.
  • Guo, H. L., Jing, X., Sun, J. Y., Hu, Y. H., Xu, Z. J., Ni, M. M., ..& Wang, T. (2019). Valproic Acid and the Liver Injury in Patients with Epilepsy: An Update. Current pharmaceutical design, 25(3), 343-351.
  • Hartmann, B., Johnsen, A. H., Ørskov, C., Adelhorst, K., Thim, L., & Holst, J. J. (2000). Structure, measurement, and secretion of human glucagon-like peptide-2. Peptides, 21(1), 73-80.
  • Jin, J., Xiong, T., Hou, X., Sun, X., Liao, J., Huang, Z., ..& Zhao, Z. (2014). Role of Nrf2 activation and NF-κB inhibition in valproic acid induced hepatotoxicity and in diammonium glycyrrhizinate induced protection in mice. Food and chemical toxicology, 73, 95-104.
  • Karaca, Ö., Sunay, F. B., Kuş, M. A., Gülcen, B., Özcan, E., Ögetürk, M., & Kuş, İ. (2014). Kadmiyum ile Oluşturulan Deneysel Karaciğer Hasarına Karşı Melatoninin Etkilerinin Biyokimyasal ve Histopatolojik Düzeylerde İncelenmesi. Fırat Tıp Derg, 19(3), 110- 115
  • Kiang,TK., Teng, XW, Karagiozov S, Surendradoss J, Chang TK, Abbott FS (2010). Role of oxidative metabolism in the effect of valproic acid on markers of cell viability, necrosis, and oxidative stress in sandwich-cultured rat hepatocytes. Toxicol Sci 118:501–509
  • Lim, D. W., Wales, P. W., Josephson, J. K., Nation, P. N., Wizzard, P. R., Sergi, C. M., .. & Turner, J. M. (2016). GlucagonLike Peptide 2 Improves Cholestasis in Parenteral Nutrition–Associated Liver Disease. Journal of Parenteral and Enteral Nutrition, 40(1), 14-21.
  • Mercan, U. (2004). Toksikolojide serbest radikallerin önemi. Yüzüncü Yıl Üniversitesi Veteriner Fakültesi Dergisi, 15(1), 9196.
  • Munroe, D. G., Gupta, A. K., Kooshesh, F., Vyas, T. B., Rizkalla, G., Wang, H., ... & McCallum, K. (1999). Prototypic G protein-coupled receptor for the intestinotrophic factor glucagon-like peptide 2. Proceedings of the National Academy of Sciences, 96(4), 1569-1573.
  • Neuman, M. G. (2019). Biomarkers of drug-induced liver toxicity. Therapeutic drug monitoring, 41(2), 227-234.
  • Springer, C., & Nappe, T. M. (2019). Anticonvulsants Toxicity. In StatPearls [Internet]. StatPearls Publishing.
  • Tong, V., Teng, X. W., Chang, T. K., & Abbott, F. S. (2005). Valproic acid I: time course of lipid peroxidation biomarkers, liver toxicity, and valproic acid metabolite levels in rats. Toxicological Sciences, 86(2), 427-435.
  • Tong, V., Teng XW, Chang TK, Abbott FS (2005b).Valproic acid I: time course of lipid peroxidation biomarkers, liver toxicity, and valproic acid metabolite levels in rats. Toxicol Sci 86:427–435
  • Zhang, W., Zhu, W., Zhang, J., Li, N., & Li, J. (2008). Protective effects of glucagon‐like peptide 2 on intestinal ischemia reperfusion rats. Microsurgery: Official Journal of the International Microsurgical Society and the European Federation of Societies for Microsurgery, 28(4), 285-290.
There are 29 citations in total.

Details

Primary Language English
Subjects Engineering
Journal Section Articles
Authors

Ozlem Oztopuz 0000-0002-1373-6311

Hakan Aylanç This is me 0000-0002-8907-3809

Müşerref Hilal Şehitoğlu 0000-0001-9040-7880

Hakan Türkön This is me 0000-0003-1888-9322

Fatih Battal 0000-0001-9040-7880

Ufuk Demir This is me 0000-0002-0020-1633

Publication Date August 31, 2020
Published in Issue Year 2020 Issue: 19

Cite

APA Oztopuz, O., Aylanç, H., Şehitoğlu, M. H., Türkön, H., et al. (2020). Glucagon-like peptide-2 May Assist to Protect against Valproic Acid Induced Hepatic Injury in Rats. Avrupa Bilim Ve Teknoloji Dergisi(19), 297-302. https://doi.org/10.31590/ejosat.711063